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Breast cancer pertinent cancer susceptibility v2.9 ATRIP Achchuthan Shanmugasundram Tag Q4_23_promote_green was removed from gene: ATRIP.
Tag Q4_23_expert_review was removed from gene: ATRIP.
Breast cancer pertinent cancer susceptibility v2.9 ATRIP Arina Puzriakova edited their review of gene: ATRIP: Added comment: After NHS Genomic Medicine Service consideration, the rating of this gene has not been changed and remains Amber. Additional comments from reviewing GLHs: 'Whilst the referenced paper does support an association with breast cancer, more studies are needed before we can consider adding this gene to any panel. The referenced paper itself comments that further replication in larger datasets is necessary to provide figures on lifetime risk, to better define the association with breast cancer and the clinic-pathological characteristics of tumors in variant carriers . Without this important information, it is too early to add the gene to a breast cancer susceptibility panel'; Changed rating: AMBER; Changed mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Breast cancer pertinent cancer susceptibility v2.8 ATRIP Arina Puzriakova Publications for gene: ATRIP were set to 36977412
Breast cancer pertinent cancer susceptibility v2.7 ATRIP Arina Puzriakova changed review comment from: As reviewed by Dmitrijs Rots (Children's Clinical University Hospital), the previously mentioned metanalysis paper has now been published (PMID: 37592023). This showed that for cases in the Breast Cancer Association Consortium (BCAC) dataset there were 13 carriers of ATRIP protein-truncating variants variants and 9 carriers in UK Biobank (UKB); in controls there were 3 carriers in BCAC and 57 in UKB (p = 0.000106).

I am uncertain whether this is sufficient evidence to add the ATRIP gene as Green to the panel and therefore this will be flagged for further GMS expert review.; to: As reviewed by Dmitrijs Rots (Children's Clinical University Hospital), the previously mentioned metanalysis paper has now been published (PMID: 37592023). This showed that for cases in the Breast Cancer Association Consortium (BCAC) dataset there were 13 carriers of ATRIP protein-truncating variants variants and 9 carriers in UK Biobank (UKB); in controls there were 3 carriers in BCAC and 57 in UKB (p = 0.000106).

This association is also now listed in Gene2Phenotype with a 'moderate' disease confidence category for breast cancer susceptibility.

I am uncertain whether this is sufficient evidence to add the ATRIP gene as Green to the panel and therefore this will be flagged for further GMS expert review.
Breast cancer pertinent cancer susceptibility v2.7 ATRIP Arina Puzriakova Tag watchlist was removed from gene: ATRIP.
Tag Q4_23_promote_green tag was added to gene: ATRIP.
Tag Q4_23_expert_review tag was added to gene: ATRIP.
Breast cancer pertinent cancer susceptibility v2.7 ATRIP Arina Puzriakova commented on gene: ATRIP: As reviewed by Dmitrijs Rots (Children's Clinical University Hospital), the previously mentioned metanalysis paper has now been published (PMID: 37592023). This showed that for cases in the Breast Cancer Association Consortium (BCAC) dataset there were 13 carriers of ATRIP protein-truncating variants variants and 9 carriers in UK Biobank (UKB); in controls there were 3 carriers in BCAC and 57 in UKB (p = 0.000106).

I am uncertain whether this is sufficient evidence to add the ATRIP gene as Green to the panel and therefore this will be flagged for further GMS expert review.
Breast cancer pertinent cancer susceptibility v2.5 ATRIP Dmitrijs Rots reviewed gene: ATRIP: Rating: GREEN; Mode of pathogenicity: Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype - please provide details in the comments; Publications: 37592023; Phenotypes: Breast cancer; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Breast cancer pertinent cancer susceptibility v2.2 ATRIP Arina Puzriakova changed review comment from: Enrichment for ATRIP variants was found in meta-analysis of breast cancer cohorts and UK Biobank. ATRIP carriers had a higher proportion of high-grade, low-stage ductal breast cancer but none of the associations with tumor characteristics were statistically significant.

Another study (PMID: 36977412) also identified three Polish women with familial breast cancer and variants in this gene including a c.69_75dup (p.Thr26Alafs∗23) frameshift insertion (not discussed further in paper) and a founder c.1152_1155del (p.Gly385Ter) frameshift deletion in two women. The founder variant was also found in validation cohorts with 42/16,085 unselected Polish breast cancer-affected individuals and 11/9,285 control subjects (OR = 2.14, 95% CI = 1.13-4.28, p = 0.02) harbouring the variant. UK Biobank data showed ATRIP loss-of-function variants among 13/15,643 breast cancer-affected individuals versus 40/157,943 control subjects (OR = 3.28, 95% CI = 1.76-6.14, p < 0.001).

Immunohistochemistry and functional studies showed the ATRIP c.1152_1155del variant allele is weakly expressed compared to the wild-type allele, and truncated ATRIP fails to perform its normal function to prevent replicative stress.
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ATRIP is currently not associated with any phenotype in OMIM or G2P. It codes for a DNA damage response protein which forms a complex with ATR. ATR-ATRIP is involved in the process that activates checkpoint signalling when single-stranded DNA is detected following the processing of DNA double-stranded breaks or stalled replication forks.; to: Enrichment for ATRIP variants was found in meta-analysis of breast cancer cohorts and UK Biobank. ATRIP carriers had a higher proportion of high-grade, low-stage ductal breast cancer but none of the associations with tumor characteristics were statistically significant (https://doi.org/10.1101/2022.06.17.22276537).

Another study (PMID: 36977412) also identified three Polish women with familial breast cancer and variants in this gene including a c.69_75dup (p.Thr26Alafs∗23) frameshift insertion (not discussed further in paper) and a founder c.1152_1155del (p.Gly385Ter) frameshift deletion in two women. The founder variant was also found in validation cohorts with 42/16,085 unselected Polish breast cancer-affected individuals and 11/9,285 control subjects (OR = 2.14, 95% CI = 1.13-4.28, p = 0.02) harbouring the variant. UK Biobank data showed ATRIP loss-of-function variants among 13/15,643 breast cancer-affected individuals versus 40/157,943 control subjects (OR = 3.28, 95% CI = 1.76-6.14, p < 0.001).

Immunohistochemistry and functional studies showed the ATRIP c.1152_1155del variant allele is weakly expressed compared to the wild-type allele, and truncated ATRIP fails to perform its normal function to prevent replicative stress.
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ATRIP is currently not associated with any phenotype in OMIM or G2P. It codes for a DNA damage response protein which forms a complex with ATR. ATR-ATRIP is involved in the process that activates checkpoint signalling when single-stranded DNA is detected following the processing of DNA double-stranded breaks or stalled replication forks.
Breast cancer pertinent cancer susceptibility v2.2 ATRIP Arina Puzriakova Classified gene: ATRIP as Amber List (moderate evidence)
Breast cancer pertinent cancer susceptibility v2.2 ATRIP Arina Puzriakova Added comment: Comment on list classification: New gene added to this panel by Lauma Freimane. More evidence is required prior to adding this gene to the panel. The metanalysis paper identified by reviewer is still at the preprint stage. The findings are detailed below but this needs to be revisited once the article has been published. This is a good candidate gene for breast cancer susceptibility but for now can only classify as Amber (with watchlist tag), awaiting peer-review and additional publication of supporting evidence.
Breast cancer pertinent cancer susceptibility v2.2 ATRIP Arina Puzriakova Gene: atrip has been classified as Amber List (Moderate Evidence).
Breast cancer pertinent cancer susceptibility v2.1 ATRIP Arina Puzriakova Tag watchlist tag was added to gene: ATRIP.
Breast cancer pertinent cancer susceptibility v2.1 ATRIP Arina Puzriakova commented on gene: ATRIP
Breast cancer pertinent cancer susceptibility v2.1 ATRIP Lauma Freimane gene: ATRIP was added
gene: ATRIP was added to Breast cancer pertinent cancer susceptibility. Sources: Literature
Mode of inheritance for gene: ATRIP was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: ATRIP were set to 36977412
Phenotypes for gene: ATRIP were set to Hereditary breast cancer
Review for gene: ATRIP was set to GREEN
gene: ATRIP was marked as current diagnostic
Added comment: Meta-analysis confirms ATRIP role in breast cancer development (https://doi.org/10.1101/2022.06.17.22276537).
Variants in ATRIP are associated with breast cancer susceptibility in the Polish population and UK Biobank.
Sources: Literature