Submissions for variant NM_032043.3(BRIP1):c.628C>T (p.Pro210Ser)

gnomAD frequency: 0.00019  dbSNP: rs150313156

Total submissions: 11

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000130394	SCV000185253	likely benign	Hereditary cancer-predisposing syndrome	2023-12-19	criteria provided, single submitter	clinical testing	This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000200420	SCV000255178	likely benign	Familial cancer of breast; Fanconi anemia complementation group J	2025-01-19	criteria provided, single submitter	clinical testing
GeneDx	RCV000590600	SCV000329150	uncertain significance	not provided	2024-02-27	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant does not alter protein structure/function; Identified in patients with breast, prostate, or colon cancer, co-occurring with a pathogenic MLH1 variant in the colon cancer patient, and also observed in unaffected controls (PMID: 26315354, 27978560, 29641532, 32866190, 33471991, 36922933); This variant is associated with the following publications: (PMID: 26315354, 31871109, 32866190, 27978560, 29641532, 33471991, 36922933)
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001290444	SCV000699733	likely benign	not specified	2024-08-08	criteria provided, single submitter	clinical testing	Variant summary: BRIP1 c.628C>T (p.Pro210Ser) results in a non-conservative amino acid change located in the Helicase-like, DEXD box c2 type domain (IPR006554) of the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. Consensus agreement among computation tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The observed variant frequency within African or African-American control individuals in the gnomAD database is approximately 6-fold of the estimated maximal expected allele frequency for a pathogenic variant in BRIP1 causing Hereditary Breast And Ovarian Cancer Syndrome phenotype (6.3e-05), suggesting that the variant is a benign polymorphism found primarily in populations of African or African-American origin. c.628C>T has been reported in the literature in individuals affected with breast cancer (e.g. Adedokun_2020) and colorectal cancer (e.g. Pearlman_2016), but also healthy controls (e.g. Ramus_2015). These reports do not provide unequivocal conclusions about association of the variant with Hereditary Breast And Ovarian Cancer Syndrome. Co-occurrences with other pathogenic variants have been reported (MLH1 c.1381A>T, p.K461X; BRCA2 c.4552delG, p.Glu1518AsnfsX25; PALB2 c.3323delA, p.Tyr1108SerfsX16), providing supporting evidence for a benign role. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 26315354, 27978560, 31871109). ClinVar contains an entry for this variant (Variation ID: 141761). Based on the evidence outlined above, the variant was classified as likely benign.
Counsyl	RCV000662423	SCV000784874	uncertain significance	Fanconi anemia complementation group J; Ovarian neoplasm	2017-01-20	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000130394	SCV001357625	uncertain significance	Hereditary cancer-predisposing syndrome	2021-01-02	criteria provided, single submitter	clinical testing	This missense variant replaces proline with serine at codon 210 of the BRIP1 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in an individual affected with colon cancer who also has a pathogenic MLH1 covariant (PMID: 27978560). This variant has been identified in 12/280104 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
Sema4, Sema4	RCV000130394	SCV002533733	uncertain significance	Hereditary cancer-predisposing syndrome	2021-06-15	criteria provided, single submitter	curation
Myriad Genetics, Inc.	RCV003315892	SCV004019410	uncertain significance	Familial cancer of breast	2023-03-01	criteria provided, single submitter	clinical testing	This variant is classified as a variant of uncertain significance as there is insufficient evidence to determine its impact on protein function and/or cancer risk.
PreventionGenetics, part of Exact Sciences	RCV004532557	SCV004120010	uncertain significance	BRIP1-related disorder	2022-11-19	criteria provided, single submitter	clinical testing	The BRIP1 c.628C>T variant is predicted to result in the amino acid substitution p.Pro210Ser. This variant was identified in an individual with colon cancer, but who also had a pathogenic variant in MLH1 (eTable 2, Pearlman et al. 2017. PubMed ID: 27978560) and in an individual with breast cancer (Table S2 - Bishop et al. 2020. PubMed ID: 32866190). This variant was also identified in a control individual from an ovarian cancer cohort study (Supplementary Table 4, Ramus et al. 2015. PubMed ID: 26315354). This variant is reported in 0.048% of alleles in individuals of African descent in gnomAD (http://gnomad.broadinstitute.org/variant/17-59886118-G-A) and has conflicting interpretations regarding its pathogenicity in ClinVar, ranging from likely benign to uncertain (https://www.ncbi.nlm.nih.gov/clinvar/variation/141761/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000590600	SCV004220731	likely benign	not provided	2023-09-05	criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000590600	SCV005878400	likely benign	not provided	2024-07-30	criteria provided, single submitter	clinical testing