Submissions for variant NM_000059.4(BRCA2):c.4271C>G (p.Ser1424Cys)

gnomAD frequency: 0.00001  dbSNP: rs80358664

Total submissions: 15

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA)	RCV000113287	SCV001161518	benign	Breast-ovarian cancer, familial, susceptibility to, 2	2019-06-18	reviewed by expert panel	curation	IARC class based on posterior probability from multifactorial likelihood analysis, thresholds for class as per Plon et al. 2008 (PMID: 18951446). Class 1 based on posterior probability = 0.000524
Labcorp Genetics (formerly Invitae), Labcorp	RCV000044384	SCV000072397	likely benign	Hereditary breast ovarian cancer syndrome	2024-02-01	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000129541	SCV000184321	likely benign	Hereditary cancer-predisposing syndrome	2021-12-29	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.
Michigan Medical Genetics Laboratories, University of Michigan	RCV000113287	SCV000195983	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2014-11-03	criteria provided, single submitter	clinical testing
GeneDx	RCV000590783	SCV000329136	likely benign	not provided	2021-06-10	criteria provided, single submitter	clinical testing	This variant is associated with the following publications: (PMID: 19491284, 21120943, 24607278, 26689913, 18824701, 25682074, 28324225, 31131967, 27535533)
Color Diagnostics, LLC DBA Color Health	RCV000129541	SCV000688863	uncertain significance	Hereditary cancer-predisposing syndrome	2023-12-30	criteria provided, single submitter	clinical testing	This missense variant replaces serine with cysteine at codon 1424 of the BRCA2 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 individuals and families affected with breast and/or ovarian cancer (PMID: 19491284, 21120943, 24607278, 25682074, 28324225). However, this variant was absent in an ovarian cancer affected member in one family (PMID: 24607278) and has been reported to have family history likelihood ratio for pathogenicity of 0.0201 from multiple carrier families (PMID: 31131967). A breast cancer case-control study also detected this variant in 2/60464 cases and 3/53458 unaffected individuals with OR=0.589 (95%CI 0.098 to 3.528) (PMID: 33471991; Leiden Open Variation Database DB-ID BRCA2_000116). This variant has been identified in 3/276480 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003389630	SCV000694761	likely benign	not specified	2024-01-12	criteria provided, single submitter	clinical testing	Variant summary: BRCA2 c.4271C>G (p.Ser1424Cys) results in a non-conservative amino acid change located in a BRCA2 repeat (IPR002093) of the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 8.2e-06 in 245096 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.4271C>G has been reported in the literature in individuals affected with breast cancer or suspected of being at risk of hereditary breast and ovarian cancer syndrome, as well as unaffected controls (e.g. Spearman_2008, Caux-Moncoutier_2011, Hafty_2009, Wong-Brown_2015, Sadowski_2017, Meisel_2017, Dorling_2021). One report showed that the variant did not co-segregate completely in a family study (4 of 5 affected family members had the variant) and identified a co-occurring BRCA1 pathogenic mutation in the same family, although no additional information was provided (Santos_2014). These reports do not provide unequivocal conclusions about association of the variant with Hereditary Breast And Ovarian Cancer Syndrome. Co-occurrence with another pathogenic variant has been reported in the NHGRI BIC database (BRCA1 c.5263_5264insC), 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: 18824701, 19471317, 19491284, 24607278, 25682074, 26689913, 28324225, 28807866, 33471991, 31131967). Seven submitters have cited clinical-significance assessments for this variant to ClinVar after 2014, and classified it as uncertain significance (n=1), likely benign (n=5), or benign (n=1, ENIGMA expert panel). Based on the evidence outlined above, the variant was classified as likely benign.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000590783	SCV000885083	likely benign	not provided	2017-07-23	criteria provided, single submitter	clinical testing
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV003149680	SCV003838155	likely benign	Breast and/or ovarian cancer	2022-06-17	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000590783	SCV004219623	uncertain significance	not provided	2023-06-10	criteria provided, single submitter	clinical testing	This variant has been characterized as being benign in a multifactorial likelihood study (PMID: 31131967 (2019)). In the published literature, the variant has been reported in individuals/families with breast and/or ovarian cancer (PMID: 19491284 (2009), 24607278 (2014), 25682074 (2015)), as well as breast cancer cases and unaffected control individuals in a large-scale breast cancer association study (PMID: 33471991, see also LOVD (http://databases.lovd.nl/shared/genes/BRCA2)). The frequency of this variant in the general population, 0.000024 (3/127176 chromosomes, http://gnomad.broadinstitute.org), is uninformative in assessment of its pathogenicity. Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded predictions that this variant is benign. Based on the available information, we are unable to determine the clinical significance of this variant.
Mayo Clinic Laboratories, Mayo Clinic	RCV000590783	SCV004226422	uncertain significance	not provided	2022-10-13	criteria provided, single submitter	clinical testing	BP6, PM2
CeGaT Center for Human Genetics Tuebingen	RCV000590783	SCV004811120	likely benign	not provided	2024-03-01	criteria provided, single submitter	clinical testing	BRCA2: BP1, BP4
All of Us Research Program, National Institutes of Health	RCV000113287	SCV004845295	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2024-02-05	criteria provided, single submitter	clinical testing	This missense variant replaces serine with cysteine at codon 1424 of the BRCA2 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 individuals and families affected with breast and/or ovarian cancer (PMID: 19491284, 21120943, 24607278, 25682074, 28324225). However, this variant was absent in an ovarian cancer affected member in one family (PMID: 24607278) and has been reported to have family history likelihood ratio for pathogenicity of 0.0201 from multiple carrier families (PMID: 31131967). A breast cancer case-control study also detected this variant in 2/60464 cases and 3/53458 unaffected individuals with OR=0.589 (95%CI 0.098 to 3.528) (PMID: 33471991; Leiden Open Variation Database DB-ID BRCA2_000116). This variant has been identified in 3/276480 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.
Breast Cancer Information Core (BIC) (BRCA2)	RCV000113287	SCV000146397	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2004-02-20	no assertion criteria provided	clinical testing
PreventionGenetics, part of Exact Sciences	RCV004732611	SCV005354877	likely benign	BRCA2-related disorder	2024-05-09	no assertion criteria provided	clinical testing	This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).