ClinVar Miner

Submissions for variant NM_000059.4(BRCA2):c.8149G>T (p.Ala2717Ser)

gnomAD frequency: 0.00127  dbSNP: rs28897747
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Total submissions: 40
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ClinGen ENIGMA BRCA1 and BRCA2 Variant Curation Expert Panel, ClinGen RCV000083145 SCV004101441 benign Breast-ovarian cancer, familial, susceptibility to, 2 2023-10-12 reviewed by expert panel curation The c.8149G>T variant in BRCA2 is a missense variant predicted to cause substitution of Alanine by Serine at amino acid 2717 (p.Ala2717Ser). The highest non-cancer, non-founder population filter allele frequency in gnomAD v2.1 (exomes only, non-cancer subset, read depth >=20) or gnomAD v3.1 (non-cancer subset, read depth >=20) is 0.001751 in the Latino/Admixed American population, which is above the ENIGMA BRCA1/2 VCEP threshold (>0.001) for BA1 (BA1 met). This BRCA2 missense variant is within a key functional domain and the computational predictor BayesDel (noAF) gives a score of -0.0816, which is below the recommended threshold of 0.18 for predicting no impact on BRCA2 via protein change. SpliceAI predictor score of 0.03 suggests that the variant has no impact on splicing (score threshold <0.10) (BP4 met). Reported by 3 calibrated studies to exhibit protein function similar to benign control variants (PMIDs: 29988080, 33609447, 32444794) (BS3 met). This variant has been observed in 2 individuals with features considered inconsistent with an FA-associated phenotype, and (Likely) Pathogenic variant seen in trans or variant is homozygous (total score 4 points) (BS2 met; Invitae internal contributor). Multifactorial likelihood ratio analysis using clinically calibrated data produced a combined LR for this variant of 2.288E-117 (based on Cosegregation LR=4.52E-08; Pathology LR=5.249E-08; Family History LR=1.995E-19; Case-Control LR=4.83E-84), below the threshold for Very strong benign evidence (LR <0.00285) (BP5_Very strong met; PMID: 18375895). In summary, this variant meets the criteria to be classified as a Benign variant for BRCA2-related cancer predisposition based on the ACMG/AMP criteria applied as specified by the ENIGMA BRCA1/2 VCEP (BA1, BP4, BS3, BS2, BP5_Very strong).
Invitae RCV000045431 SCV000073444 benign Hereditary breast ovarian cancer syndrome 2024-02-01 criteria provided, single submitter clinical testing
Counsyl RCV000083145 SCV000154080 benign Breast-ovarian cancer, familial, susceptibility to, 2 2014-03-05 criteria provided, single submitter literature only
GeneDx RCV000120361 SCV000167406 benign not specified 2013-11-26 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.
Ambry Genetics RCV000129099 SCV000183810 benign Hereditary cancer-predisposing syndrome 2014-11-19 criteria provided, single submitter clinical testing This alteration is classified as benign based on a combination of the following: 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 RCV000083145 SCV000196011 benign Breast-ovarian cancer, familial, susceptibility to, 2 2014-11-03 criteria provided, single submitter clinical testing
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario RCV000735609 SCV000219404 benign Breast and/or ovarian cancer 2023-04-17 criteria provided, single submitter clinical testing
Eurofins Ntd Llc (ga) RCV000120361 SCV000226714 benign not specified 2014-08-15 criteria provided, single submitter clinical testing
Vantari Genetics RCV000129099 SCV000267024 likely benign Hereditary cancer-predisposing syndrome 2015-12-18 criteria provided, single submitter clinical testing
Illumina Laboratory Services, Illumina RCV000083145 SCV000383777 likely benign Breast-ovarian cancer, familial, susceptibility to, 2 2017-04-27 criteria provided, single submitter clinical testing This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign.
Illumina Laboratory Services, Illumina RCV000280295 SCV000383778 likely benign Fanconi anemia complementation group D1 2017-04-27 criteria provided, single submitter clinical testing This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000045431 SCV000494362 benign Hereditary breast ovarian cancer syndrome 2014-04-03 criteria provided, single submitter clinical testing
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine RCV000120361 SCV000538490 uncertain significance not specified 2016-03-28 criteria provided, single submitter clinical testing Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Clinvar: 10 labs classify as LB/Ben; ExAC: 0.2% (118/66734) European chromosomes
Fulgent Genetics, Fulgent Genetics RCV000083145 SCV000575734 likely benign Breast-ovarian cancer, familial, susceptibility to, 2 2015-09-16 criteria provided, single submitter clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories RCV000034461 SCV000602845 benign not provided 2023-10-18 criteria provided, single submitter clinical testing
Color Diagnostics, LLC DBA Color Health RCV000129099 SCV000683946 likely benign Hereditary cancer-predisposing syndrome 2015-02-11 criteria provided, single submitter clinical testing
Genome Diagnostics Laboratory, University Medical Center Utrecht RCV000083145 SCV000743343 benign Breast-ovarian cancer, familial, susceptibility to, 2 2015-08-24 criteria provided, single submitter clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center RCV000083145 SCV000744534 benign Breast-ovarian cancer, familial, susceptibility to, 2 2015-09-21 criteria provided, single submitter clinical testing
Preventiongenetics, part of Exact Sciences RCV000034461 SCV000805774 likely benign not provided 2017-03-21 criteria provided, single submitter clinical testing
Mendelics RCV000083145 SCV001139206 likely benign Breast-ovarian cancer, familial, susceptibility to, 2 2019-05-28 criteria provided, single submitter clinical testing
Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden RCV000034461 SCV002010316 benign not provided 2021-11-03 criteria provided, single submitter clinical testing
National Health Laboratory Service, Universitas Academic Hospital and University of the Free State RCV000045431 SCV002025842 benign Hereditary breast ovarian cancer syndrome 2022-04-19 criteria provided, single submitter clinical testing
Genetic Services Laboratory, University of Chicago RCV000120361 SCV002070556 likely benign not specified 2021-09-22 criteria provided, single submitter clinical testing
Sema4, Sema4 RCV000129099 SCV002531916 benign Hereditary cancer-predisposing syndrome 2020-09-08 criteria provided, single submitter curation
CeGaT Center for Human Genetics Tuebingen RCV000034461 SCV002545114 likely benign not provided 2023-09-01 criteria provided, single submitter clinical testing BRCA2: BP1, BS3:Supporting, BS1
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital RCV000120361 SCV002551768 benign not specified 2023-08-15 criteria provided, single submitter clinical testing
Biesecker Lab/Clinical Genomics Section, National Institutes of Health RCV000034461 SCV000043228 probably not pathogenic not provided 2012-07-13 no assertion criteria provided research Converted during submission to Likely benign.
ITMI RCV000120361 SCV000084513 not provided not specified 2013-09-19 no assertion provided reference population
Sharing Clinical Reports Project (SCRP) RCV000083145 SCV000115219 benign Breast-ovarian cancer, familial, susceptibility to, 2 2012-05-01 no assertion criteria provided clinical testing
Breast Cancer Information Core (BIC) (BRCA2) RCV000083145 SCV000147282 benign Breast-ovarian cancer, familial, susceptibility to, 2 2002-05-29 no assertion criteria provided clinical testing
Pathway Genomics RCV000083145 SCV000207343 benign Breast-ovarian cancer, familial, susceptibility to, 2 2014-11-06 no assertion criteria provided clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System RCV001353905 SCV000592175 benign Malignant tumor of breast no assertion criteria provided clinical testing The p.Ala2717Ser variant has been identified in five individuals from our laboratory, 36 times in the UMD-BRCA2 database and 112 times in the BIC database. The variant was identified in 19 of 7810 proband chromosomes in individuals with breast, ovarian and prostate cancer patients (Edwards 2003, Diez 2003, Lubinski 2004, Salazar 2006, Giannini 2006, Soegaard 2008, Caux-Moncoutier 2009, Capanu 2011). However, an inadequate number of control chromosomes were tested to establish the variants frequency in the general population. This variant is listed in dbSNP database as coming from a "clinical source" (ID#: rs28897747) and was identified in more than one population with an average heterozygosity of 0.004+/-0.046, increasing the likelihood that this is a low frequency benign variant. The Ala2717 residue is not highly conserved in mammals and neither computational analyses (SIFT, AlignGVGD) nor other in silico protein modeling predictions (Karchin 2008, Spurdle 2008) suggest a high likelihood of impact to the protein. However, this information is not predictive enough to rule out pathogenicity. Finally, this variant was identified in at least three individuals in the UMD database who had a second premature truncating variant that is expected to be pathogenic, increasing the likelihood that the p.Ala2712Ser variant is not clinically significant. In summary, based on the above information this variant is classified as Benign.
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen RCV000083145 SCV000733313 benign Breast-ovarian cancer, familial, susceptibility to, 2 no assertion criteria provided clinical testing
Mayo Clinic Laboratories, Mayo Clinic RCV000034461 SCV000778717 benign not provided 2015-10-07 no assertion criteria provided clinical testing
True Health Diagnostics RCV000129099 SCV000787952 likely benign Hereditary cancer-predisposing syndrome 2018-01-05 no assertion criteria provided clinical testing
Foulkes Cancer Genetics LDI, Lady Davis Institute for Medical Research RCV000735609 SCV000863747 uncertain significance Breast and/or ovarian cancer 2001-02-15 no assertion criteria provided clinical testing
Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC) RCV000034461 SCV001799396 likely benign not provided no assertion criteria provided clinical testing
Clinical Genetics Laboratory, Department of Pathology, Netherlands Cancer Institute RCV000120361 SCV001906396 benign not specified no assertion criteria provided clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+ RCV000120361 SCV001954450 benign not specified no assertion criteria provided clinical testing
BRCAlab, Lund University RCV000083145 SCV004243802 benign Breast-ovarian cancer, familial, susceptibility to, 2 2020-03-02 no assertion criteria provided clinical testing

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