Submissions for variant NM_000059.4(BRCA2):c.3515C>T (p.Ser1172Leu)

gnomAD frequency: 0.00146  dbSNP: rs80358600

Total submissions: 33

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA)	RCV000077306	SCV000244437	benign	Breast-ovarian cancer, familial, susceptibility to, 2	2015-08-10	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 = 0.000000315
Labcorp Genetics (formerly Invitae), Labcorp	RCV000044213	SCV000072226	benign	Hereditary breast ovarian cancer syndrome	2024-02-01	criteria provided, single submitter	clinical testing
GeneDx	RCV000074526	SCV000108611	benign	not specified	2016-12-09	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.
Michigan Medical Genetics Laboratories, University of Michigan	RCV000077306	SCV000195976	benign	Breast-ovarian cancer, familial, susceptibility to, 2	2014-11-03	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000162770	SCV000213247	benign	Hereditary cancer-predisposing syndrome	2014-08-06	criteria provided, single submitter	clinical testing	This alteration is classified as 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.
Counsyl	RCV000077306	SCV000220437	likely benign	Breast-ovarian cancer, familial, susceptibility to, 2	2014-06-20	criteria provided, single submitter	literature only
Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia	RCV000044213	SCV000296853	likely benign	Hereditary breast ovarian cancer syndrome	2015-09-24	criteria provided, single submitter	clinical testing
Eurofins Ntd Llc (ga)	RCV000074526	SCV000333319	benign	not specified	2015-07-29	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000077306	SCV000383683	likely benign	Breast-ovarian cancer, familial, susceptibility to, 2	2017-04-28	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	RCV000303693	SCV000383684	likely benign	Fanconi anemia complementation group D1	2017-04-28	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.
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000074526	SCV000538458	benign	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: ExAC: 1.4% (90/6610) Finnish chromosomes
Department of Pathology and Molecular Medicine, Queen's University	RCV000074526	SCV000588090	benign	not specified	2017-04-20	criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000074526	SCV000602860	benign	not specified	2017-02-08	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000162770	SCV000683564	benign	Hereditary cancer-predisposing syndrome	2015-08-05	criteria provided, single submitter	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000077306	SCV000744439	benign	Breast-ovarian cancer, familial, susceptibility to, 2	2015-09-21	criteria provided, single submitter	clinical testing
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV000770718	SCV000902196	likely benign	Breast and/or ovarian cancer	2016-11-11	criteria provided, single submitter	clinical testing
Mendelics	RCV000077306	SCV001139065	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	RCV000034437	SCV002010382	benign	not provided	2021-11-03	criteria provided, single submitter	clinical testing
Genetic Services Laboratory, University of Chicago	RCV000074526	SCV002068086	likely benign	not specified	2021-07-21	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000162770	SCV002533804	benign	Hereditary cancer-predisposing syndrome	2021-02-01	criteria provided, single submitter	curation
CeGaT Center for Human Genetics Tuebingen	RCV000034437	SCV002545110	likely benign	not provided	2024-08-01	criteria provided, single submitter	clinical testing	BRCA2: BP4, BS2
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV000074526	SCV002550322	benign	not specified	2023-08-15	criteria provided, single submitter	clinical testing
Institute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C.	RCV000044213	SCV005415557	benign	Hereditary breast ovarian cancer syndrome	2024-09-03	criteria provided, single submitter	clinical testing	The missense variant NM_000059.4(BRCA2):c.3515C>T (p.Ser1172Leu) has been reported to ClinVar as Benign with a status of (3 stars) reviewed by expert panel (Variation ID 41546 as of 2024-08-01). There is a large physicochemical difference between serine and leucine, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. The gene BRCA2 has a low rate of benign missense variation as indicated by a high missense variants Z-Score of 1.00. The gene BRCA2 contains 146 pathogenic missense variants, indicating that missense variants are a common mechanism of disease in this gene. For these reasons, this variant has been classified as Benign.
Institute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C.	RCV000162770	SCV005415559	likely benign	Hereditary cancer-predisposing syndrome	2024-09-10	criteria provided, single submitter	clinical testing	The synonymous variant NM_000038.6(APC):c.5250C>T (p.Val1750=) has been reported to ClinVar as Benign/Likely benign with a status of (2 stars) criteria provided, multiple submitters, no conflicts (Variation ID 184668 as of 2024-08-01). The p.Val1750= variant is observed in 12/10,044 (0.1195%) alleles from individuals of gnomAD Ashkenazi Jewish background in gnomAD, which is greater than expected for the disorder. The p.Val1750= variant is not predicted to disrupt an existing splice site. The p.Val1750= variant results in a substitution of a base that is not predicted conserved by GERP++ and PhyloP. For these reasons, this variant has been classified as Likely Benign.
Biesecker Lab/Clinical Genomics Section, National Institutes of Health	RCV000034437	SCV000043205	variant of unknown significance	not provided	2012-07-13	flagged submission	research	Converted during submission to Uncertain significance.
Sharing Clinical Reports Project (SCRP)	RCV000077306	SCV000109103	benign	Breast-ovarian cancer, familial, susceptibility to, 2	2008-10-19	no assertion criteria provided	clinical testing
Breast Cancer Information Core (BIC) (BRCA2)	RCV000077306	SCV000146251	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2002-05-29	no assertion criteria provided	clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV000074526	SCV000591865	benign	not specified		no assertion criteria provided	clinical testing
Clinical Genetics Laboratory, Department of Pathology, Netherlands Cancer Institute	RCV000074526	SCV001906087	benign	not specified		no assertion criteria provided	clinical testing
Genome Diagnostics Laboratory, University Medical Center Utrecht	RCV000074526	SCV001927906	benign	not specified		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000074526	SCV001951099	benign	not specified		no assertion criteria provided	clinical testing
BRCAlab, Lund University	RCV000077306	SCV004243608	benign	Breast-ovarian cancer, familial, susceptibility to, 2	2020-03-02	no assertion criteria provided	clinical testing
PreventionGenetics, part of Exact Sciences	RCV004532504	SCV004755586	benign	BRCA2-related disorder	2019-04-16	no assertion criteria provided	clinical testing	This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).