Submissions for variant NM_000059.4(BRCA2):c.8010G>A (p.Ser2670=)

gnomAD frequency: 0.00003  dbSNP: rs146430937

Total submissions: 22

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA)	RCV000495522	SCV000579152	likely benign	Breast-ovarian cancer, familial, susceptibility to, 2	2017-06-29	reviewed by expert panel	curation	Synonymous substitution variant, with low bioinformatic likelihood to result in a splicing aberration (Splicing prior probability 0.02; http://priors.hci.utah.edu/PRIORS/).
Ambry Genetics	RCV000162665	SCV000213109	likely benign	Hereditary cancer-predisposing syndrome	2014-11-04	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	RCV001083953	SCV000253044	benign	Hereditary breast ovarian cancer syndrome	2025-01-26	criteria provided, single submitter	clinical testing
GeneDx	RCV000428428	SCV000512391	benign	not specified	2015-05-29	criteria provided, single submitter	clinical testing	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.
Color Diagnostics, LLC DBA Color Health	RCV000162665	SCV000683936	benign	Hereditary cancer-predisposing syndrome	2016-03-06	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000586244	SCV000695122	likely benign	not provided	2017-05-22	criteria provided, single submitter	clinical testing	Variant summary: The BRCA2 c.8010G>A (p.Ser2670Ser) variant involves the alteration of a non-conserved nucleotide, resulting in a synonymous change. One in silico tool predicts a damaging outcome for this variant. 4/5 splice prediction tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. This variant was found in 11/120304 control chromosomes at a frequency of 0.0000914, which does not exceed the estimated maximal expected allele frequency of a pathogenic BRCA2 variant (0.0007503). The variant has been reported in the literature, without strong evidence for causality. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as likely benign/benign, with one database citing the variant to co-occur with a pathogenic BRCA1 variant in one individual (BRCA1 c.3228_3229delAG (p.Gly1077AlafsX8)). Taken together, this variant is classified as likely benign.
Counsyl	RCV000495522	SCV000785077	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2017-04-05	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000586244	SCV000889148	likely benign	not provided	2021-11-06	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000586244	SCV001148994	likely benign	not provided	2024-12-01	criteria provided, single submitter	clinical testing	BRCA2: BP4, BP7
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000586244	SCV001471791	likely benign	not provided	2022-12-27	criteria provided, single submitter	clinical testing
National Health Laboratory Service, Universitas Academic Hospital and University of the Free State	RCV001083953	SCV002025839	likely benign	Hereditary breast ovarian cancer syndrome	2022-04-19	criteria provided, single submitter	clinical testing
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV000735607	SCV002043494	likely benign	Breast and/or ovarian cancer	2023-05-24	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000162665	SCV002531905	likely benign	Hereditary cancer-predisposing syndrome	2021-02-19	criteria provided, single submitter	curation
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV000428428	SCV002551746	likely benign	not specified	2025-03-04	criteria provided, single submitter	clinical testing
KCCC/NGS Laboratory, Kuwait Cancer Control Center	RCV000495522	SCV004016896	likely benign	Breast-ovarian cancer, familial, susceptibility to, 2	2023-07-07	criteria provided, single submitter	clinical testing
Molecular Diagnostics Laboratory, Catalan Institute of Oncology	RCV000162665	SCV005902066	likely benign	Hereditary cancer-predisposing syndrome	2024-12-02	criteria provided, single submitter	clinical testing	BS1_Supporting, BP4, BP7 c.8010G>A, located in a (potentially) clinically important functional domain of BRCA2, is predicted to result in no splicing alteration (according to SpliceAI) and no amino acid change, p.(Ser2670=) (BP4, BP7). The variant allele was found in 14/117809 alleles, with a filter allele frequency of 0,006% at 99% confidence, within the European (non-Finnish) population in the gnomAD v2.1.1 database (non-cancer data set) (BS1_Supporting). To our knowledge, neither relevant clinical data nor well-stablished functional studies have been reported for this variant. In addition, the variant was also identified in the following databases: BRCA Exchange (Likely benign: Synonymous substitution variant, with low bioinformatic likelihood to result in a splicing aberration (Splicing prior probability 0.02; http://priors.hci.utah.edu/PRIORS/)), ClinVar (3x benign, 15x likely benign, 1x uncertain significance) and LOVD (1x benign, 5x likely benign, 10x uncertain significance). Based on currently available information, the variant c.8010G>A should be considered a likely benign variant.
Foulkes Cancer Genetics LDI, Lady Davis Institute for Medical Research	RCV000735607	SCV000863745	likely benign	Breast and/or ovarian cancer	2014-03-06	no assertion criteria provided	clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV000586244	SCV001553667	likely benign	not provided		no assertion criteria provided	clinical testing	The BRCA2 p.Ser2670= variant was identified in 2 of 324 proband chromosomes (frequency: 0.006) from individuals or families with breast or ovarian cancer (Muendlein 2015, Zanella 2017). The variant was also identified in dbSNP (ID: rs146430937) as "With other allele”, ClinVar (classified as benign by Invitae, GeneDx and Color; as likely benign by 4 submitters; as uncertain significance by Counsyl), COGR, Cosmic (1x in large intestine tissue), and in UMD-LSDB (12x as neutral), databases. In UMD the variant was identified with a co-occurring pathogenic BRCA1 variant (c.3228_3229delAG, p.Gly1077AlafsX8), increasing the likelihood that the p.Ser2670= variant does not have clinical significance. The variant was not identified in BIC Database, ARUP Laboratories, or Zhejiang University databases. The variant was identified in control databases in 16 of 245594 chromosomes at a frequency of 0.00007 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: European in 14 of 111296 chromosomes (freq: 0.0001), and South Asian in 2 of 30750 chromosomes (freq: 0.00007), while the variant was not observed in the African, Other, Latino, Ashkenazi Jewish, East Asian, or Finnish populations. A classification model for BRCA2 DNA binding domain missense variants based on homology-directed repair activity study shows the variant may disrupt the helical-OB1 interface (Guidugli 2013). The p.Ser2670= variant is not expected to have clinical significance because it does not result in a change of amino acid and is not located in a known consensus splice site. In addition, in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) do not predict a difference in splicing. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time although we would lean towards a more benign role for this variant. This variant is classified as likely benign.
Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	RCV000586244	SCV001797751	likely benign	not provided		no assertion criteria provided	clinical testing
Institute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C.	RCV001083953	SCV001950166	likely benign	Hereditary breast ovarian cancer syndrome	2021-09-15	no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000586244	SCV001969850	likely benign	not provided		no assertion criteria provided	clinical testing
PreventionGenetics, part of Exact Sciences	RCV004544481	SCV004777711	likely benign	BRCA2-related disorder	2024-02-07	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).