Submissions for variant NM_000059.4(BRCA2):c.3581G>A (p.Gly1194Asp)

gnomAD frequency: 0.00003  dbSNP: rs28897721

Total submissions: 23

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA)	RCV000077309	SCV000244439	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 = 0.0000646
Labcorp Genetics (formerly Invitae), Labcorp	RCV001084719	SCV000072240	benign	Hereditary breast ovarian cancer syndrome	2024-01-17	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000131681	SCV000186717	likely benign	Hereditary cancer-predisposing syndrome	2018-10-26	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.
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV000735541	SCV000219329	likely benign	Breast and/or ovarian cancer	2017-02-07	criteria provided, single submitter	clinical testing
Counsyl	RCV000077309	SCV000487793	benign	Breast-ovarian cancer, familial, susceptibility to, 2	2015-11-20	criteria provided, single submitter	clinical testing
GeneDx	RCV000034439	SCV000518131	likely benign	not provided	2020-05-27	criteria provided, single submitter	clinical testing	This variant is associated with the following publications: (PMID: 25980754, 24323938, 22703879, 21990134, 17924331, 26689913, 17257844, 27150160, 26155992)
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000440462	SCV000694707	benign	not specified	2020-11-09	criteria provided, single submitter	clinical testing	Variant summary: BRCA2 c.3581G>A (p.Gly1194Asp) results in a non-conservative amino acid change located in the BRCA2 repeat region 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 8.7e-05 in 252186 control chromosomes. This frequency is not significantly higher than expected for a pathogenic variant in BRCA2 causing Hereditary Breast And Ovarian Cancer Syndrome (8.7e-05 vs 0.00075), allowing no conclusion about variant significance. c.3581G>A, has been reported in the literature in individuals affected with Breast and Ovarian Cancer (e.g. Alsop 2012, Musolino 2007), without strong evidence for pathogenicity. The variant was predicted to be neutral with a multifactorial probability model, based on tumor pathology, clinical histories, family studies and co-occurrence with deleterious mutations (Easton 2007). In addition, UMD BRCA2 database classified this variant as 'likely neutral'. These report(s) do not provide unequivocal conclusions about association of the variant with Hereditary Breast And Ovarian Cancer Syndrome. At-least two co-occurrences with other pathogenic variant(s) have been observed (BRCA2 c.5130_5133delTGTA, p.Y1710* at our laboratory; TP53 c.524G>A , p.R175H in a family with Li-Fraunemi syndrome, Zampiga_2016), providing supporting evidence for a benign role. Nine clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation (benign, n=3, likely benign, n=5, VUS, n=1). Based on the lack of any actionable evidence supporting a pathogenic outcome as outlined above, the variant was classified as benign.
Color Diagnostics, LLC DBA Color Health	RCV000131681	SCV000902800	likely benign	Hereditary cancer-predisposing syndrome	2015-11-08	criteria provided, single submitter	clinical testing
Mendelics	RCV000077309	SCV001139068	likely benign	Breast-ovarian cancer, familial, susceptibility to, 2	2019-05-28	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV001111917	SCV001269525	uncertain significance	Fanconi anemia complementation group D1	2019-05-20	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 did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Illumina Laboratory Services, Illumina	RCV000077309	SCV001269526	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2019-05-20	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. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Sema4, Sema4	RCV000131681	SCV002533810	likely benign	Hereditary cancer-predisposing syndrome	2021-04-28	criteria provided, single submitter	curation
CeGaT Center for Human Genetics Tuebingen	RCV000034439	SCV003917270	likely benign	not provided	2023-05-01	criteria provided, single submitter	clinical testing	BRCA2: BP2, BP4
Institute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C.	RCV001084719	SCV005045461	likely benign	Hereditary breast ovarian cancer syndrome	2024-03-14	criteria provided, single submitter	clinical testing
Biesecker Lab/Clinical Genomics Section, National Institutes of Health	RCV000034439	SCV000043207	variant of unknown significance	not provided	2012-07-13	no assertion criteria provided	research	Converted during submission to Uncertain significance.
Sharing Clinical Reports Project (SCRP)	RCV000077309	SCV000109106	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2008-05-02	no assertion criteria provided	clinical testing
Breast Cancer Information Core (BIC) (BRCA2)	RCV000077309	SCV000146262	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	RCV000077309	SCV000591870	benign	Breast-ovarian cancer, familial, susceptibility to, 2		no assertion criteria provided	clinical testing	The p.Gly1194Asp variant has been identified in 1 out of 132 proband chromosomes (frequency 0.008) in individuals with breast cancer phenotype; however no normal population controls were included in this study (Musolino 2007). It is also listed in dbSNP database presented “with untested allele” (ID#: rs28897721) while no frequency information is provided, therefore representing a rare allele. The variant is also listed in the BIC database 7x as a variant of unknown clinical significance and 4x in the UMD database as a likely neutral variant and was observed once in conjunction with a second "unclassified variant". The p.Gly1194 residue is not conserved in mammals and computational analyses (SIFT, AlignGVGD) do not suggest a high likelihood of impact to the protein. However, this information is not predictive enough to rule out pathogenicity. In addition in silico risk assessment analysis of this variant do not suggest clinical significance (Easton 2007, Lindor 2011). Our laboratory has previously identified this variant in one individual who also had a pathogenic variant in BRCA1 increasing the likelihood this variant is benign. In summary, 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 Benign.
Foulkes Cancer Genetics LDI, Lady Davis Institute for Medical Research	RCV000735541	SCV000863679	uncertain significance	Breast and/or ovarian cancer		no assertion criteria provided	clinical testing
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	RCV000440462	SCV001741607	benign	not specified		no assertion criteria provided	clinical testing
Clinical Genetics Laboratory, Department of Pathology, Netherlands Cancer Institute	RCV000440462	SCV001905984	benign	not specified		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000440462	SCV001957038	benign	not specified		no assertion criteria provided	clinical testing
PreventionGenetics, part of Exact Sciences	RCV004532505	SCV004755117	likely benign	BRCA2-related disorder	2023-01-11	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).