Submissions for variant NM_000059.4(BRCA2):c.5612G>A (p.Ser1871Asn)

gnomAD frequency: 0.00019  dbSNP: rs80358782

Total submissions: 16

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000044695	SCV000072708	likely benign	Hereditary breast ovarian cancer syndrome	2024-01-21	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000130705	SCV000185592	likely benign	Hereditary cancer-predisposing syndrome	2019-12-23	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.
Eurofins Ntd Llc (ga)	RCV000588661	SCV000225159	uncertain significance	not provided	2015-04-24	criteria provided, single submitter	clinical testing
GeneDx	RCV000588661	SCV000278862	uncertain significance	not provided	2024-05-14	criteria provided, single submitter	clinical testing	Observed in individuals with breast or prostate cancer (PMID: 12474142, 18284688, 25777348, 36329109); In silico analysis supports that this missense variant does not alter protein structure/function; Also known as 5840G>A; This variant is associated with the following publications: (PMID: 12474142, 25777348, 18284688, 10923033, 29884841, 35264596, 31853058, 31911673, 32377563, 33471991, 36329109)
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000588661	SCV000600648	likely benign	not provided	2022-09-06	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000215831	SCV000694883	uncertain significance	not specified	2024-01-29	criteria provided, single submitter	clinical testing	Variant summary: BRCA2 c.5612G>A (p.Ser1871Asn) results in a conservative amino acid change located in the BRCA2 repeat; IPR002093 of the encoded protein sequence. Five of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 3.2e-05 in 1610562 control chromosomes, predominantly at a frequency of 0.00057 within the African or African-American subpopulation in the gnomAD database (v4.0.0). This frequency is not significantly higher than estimated for a pathogenic variant in BRCA2 causing Hereditary Breast And Ovarian Cancer Syndrome (3.2e-05 vs 0.00075), allowing no conclusion about variant significance. c.5612G>A has been reported in the literature in individuals affected with Breast And Ovarian Cancer (Edwards_2003, Lee_2008, El Saghir_2015, Dorling_2021) as well as in individuals without Breast And Ovarian Cancer (FLOSSIES database, Dorling_2021). These reports do not provide unequivocal conclusions about association of the variant with Hereditary Breast And Ovarian Cancer Syndrome. Co-occurrences with other pathogenic variant(s) have been reported ( BRCA1 c.798_799delTT, p.Ser267LysfsX19), 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: 12474142, 18284688, 25777348, 33471991). ClinVar contains an entry for this variant (Variation ID: 51891). Based on the evidence outlined above, the variant was classified as uncertain significance.
Counsyl	RCV000077355	SCV000785315	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2017-07-05	criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000588661	SCV000883485	uncertain significance	not provided	2017-06-27	criteria provided, single submitter	clinical testing	The BRCA2 c.5612G>A; p.Ser1871Asn variant (rs80358782) has been reported in individuals with early-onset prostate cancer or breast cancer (Edwards 2003, El Saghir 2015, Lee 2008). This variant is reported multiple times in ClinVar as uncertain (Variation ID: 51891), and observed in general population databases with overall allele frequencies of 0.02 percent (1/5008 alleles, 1000 Genomes Project), and 0.006 percent (17/273156 alleles, Genome Aggregation Database). The serine at codon 1871 is weakly conserved, and computational algorithms (SIFT, PolyPhen2, MutationTaster, Prior Probabilities) predict this variant to be tolerated. However, due to the limited information regarding p.Ser1871Asn, its clinical significance in uncertain at this time. REFERENCES Link to ClinVar database for p.Ser1871Asn: https://www.ncbi.nlm.nih.gov/clinvar/variation/51891/ Edwards SM et al. Two percent of men with early-onset prostate cancer harbor germline mutations in the BRCA2 gene. Am J Hum Genet. 2003 Jan;72(1):1-12. El Saghir NS et al. BRCA1 and BRCA2 mutations in ethnic Lebanese Arab women with high hereditary risk breast cancer. Oncologist. 2015 Apr;20(4):357-64. Lee E et al. Evaluation of unclassified variants in the breast cancer susceptibility genes BRCA1 and BRCA2 using five methods: results from a population-based study of young breast cancer patients. Breast Cancer Res. 2008;10(1):R19.
Color Diagnostics, LLC DBA Color Health	RCV000130705	SCV000903134	likely benign	Hereditary cancer-predisposing syndrome	2016-01-06	criteria provided, single submitter	clinical testing
Mendelics	RCV003492358	SCV001139117	likely benign	Hereditary cancer	2024-01-23	criteria provided, single submitter	clinical testing
Genetics Program, Instituto Nacional de Cancer	RCV000044695	SCV002515120	uncertain significance	Hereditary breast ovarian cancer syndrome	2021-11-01	criteria provided, single submitter	research
Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein	RCV000077355	SCV003807811	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2022-12-22	criteria provided, single submitter	clinical testing	ACMG classification criteria: PM2 supporting, BP4 supporting
University of Washington Department of Laboratory Medicine, University of Washington	RCV000130705	SCV003848954	likely benign	Hereditary cancer-predisposing syndrome	2023-03-23	criteria provided, single submitter	curation	Missense variant in a coldspot region where missense variants are very unlikely to be pathogenic (PMID:31911673).
Sharing Clinical Reports Project (SCRP)	RCV000077355	SCV000109152	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2008-05-22	no assertion criteria provided	clinical testing
Breast Cancer Information Core (BIC) (BRCA2)	RCV000077355	SCV000146644	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2004-02-20	no assertion criteria provided	clinical testing
Genetic Services Laboratory, University of Chicago	RCV000215831	SCV003839284	uncertain significance	not specified	2022-06-06	no assertion criteria provided	clinical testing	DNA sequence analysis of the BRCA2 gene demonstrated a sequence change, c.5612G>A, in exon 11 that results in an amino acid change, p.Ser1871Asn. This sequence change has been described in the gnomAD database with a frequency of 0.069% in the African/African American subpopulation (dbSNP rs80358782). The p.Ser1871Asn change affects a poorly conserved amino acid residue located in a domain of the BRCA2 protein that is known to be functional. The p.Ser1871Asn substitution appears to be benign using several in-silico pathogenicity prediction tools (SIFT, PolyPhen2, Align GVGD, REVEL). This sequence change has been previously described in individuals with BRCA2-related cancers, as well as in individuals with no history of cancer (PMID: 12474142, 25777348, 18284688, 33471991, FLOSSIES database https://whi.color.com/variant/13-32914104-G-A). Due to insufficient evidences and the lack of functional studies, the clinical significance of the p.Ser1871Asn change remains unknown at this time.