Submissions for variant NM_000059.4(BRCA2):c.8905G>A (p.Val2969Met)

gnomAD frequency: 0.00019  dbSNP: rs59004709

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)	RCV000077456	SCV000244488	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 = 0.000011
Invitae	RCV001080800	SCV000073664	benign	Hereditary breast ovarian cancer syndrome	2024-02-01	criteria provided, single submitter	clinical testing
Counsyl	RCV000077456	SCV000154091	likely benign	Breast-ovarian cancer, familial, susceptibility to, 2	2014-03-20	criteria provided, single submitter	literature only
GeneDx	RCV001719798	SCV000210675	likely benign	not provided	2020-10-09	criteria provided, single submitter	clinical testing	This variant is associated with the following publications: (PMID: 21232165, 18559594, 21965345, 18375895, 20104584, 25948282, 26780556, 24323938, 28324225, 28678401, 17924331, 21990134, 29884841)
Ambry Genetics	RCV000163015	SCV000213503	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: 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.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV001719798	SCV000883493	likely benign	not provided	2020-06-02	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000163015	SCV000910612	likely benign	Hereditary cancer-predisposing syndrome	2015-07-23	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000077456	SCV001270520	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2018-01-13	criteria provided, single submitter	clinical testing	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
Illumina Laboratory Services, Illumina	RCV001112821	SCV001270521	uncertain significance	Fanconi anemia complementation group D1	2018-01-13	criteria provided, single submitter	clinical testing	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden	RCV001719798	SCV002010298	benign	not provided	2021-11-03	criteria provided, single submitter	clinical testing
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV001798242	SCV002043631	uncertain significance	Breast and/or ovarian cancer	2020-06-25	criteria provided, single submitter	clinical testing
Genetic Services Laboratory, University of Chicago	RCV000168609	SCV002070805	likely benign	not specified	2019-06-25	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000163015	SCV002531986	likely benign	Hereditary cancer-predisposing syndrome	2021-07-12	criteria provided, single submitter	curation
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV000168609	SCV002551837	benign	not specified	2023-08-15	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV001719798	SCV004132995	benign	not provided	2023-02-01	criteria provided, single submitter	clinical testing	BRCA2: BP4, BS1, BS2
All of Us Research Program, National Institutes of Health	RCV000077456	SCV004846091	likely benign	Breast-ovarian cancer, familial, susceptibility to, 2	2024-01-11	criteria provided, single submitter	clinical testing
Sharing Clinical Reports Project (SCRP)	RCV000077456	SCV000109254	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2006-11-06	no assertion criteria provided	clinical testing
Breast Cancer Information Core (BIC) (BRCA2)	RCV000077456	SCV000147483	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	RCV001353409	SCV000592236	uncertain significance	Malignant tumor of breast		no assertion criteria provided	clinical testing	The BRCA2 p.Val2969Met variant was identified in 6 of 9554 proband chromosomes (frequency: 0.001) from individuals or families with hereditary breast and ovarian cancer and was not identified in 80 control chromosomes from healthy individuals (Akbari 2011, Borg 2010, Soegaard 2008, Stegel 2011, Kluska 2015). The variant was also identified by our laboratory in 1 individual with hereditary breast and ovarian cancer. The variant was also identified in dbSNP (ID: rs59004709) as “other”, Clinvitae database (as benign), Fanconi Anemia Mutation Database -LOVD (3x, as predicted neutral 2x and predicted deleterious 1x), LOVD-IARC database (as not pathogenic), ARUP Laboratories BRCA Mutations Database (as not pathogenic), the ClinVar database (as benign, reviewed by an expert panel), GeneInsight COGR database (as “benign”, “likely benign”, and “unknown significance”, by clinical laboratories), the BIC database (24x with unknown clinical importance), and UMD (23x with a “likely neutral” classification). This variant was identified in the 1000 Genomes Project in 3 of 5000 chromosomes (frequency: 0.0006), NHLBI GO Exome Sequencing Project in 2 of 8600 European American alleles and 1 of 4406 African American alleles, and in the Exome Aggregation Consortium database (March 14, 2016) in 49 of 120422 chromosomes (freq. 0.0004) in the following populations: European (Non-Finnish) in 41 of 66196 chromosomes (freq. 0.0006), European (Finnish) in 4 of 6614 chromosomes (freq. 0.0006), and African in 4 of 10180 chromosomes (freq. 0.0004), but was not seen in East Asian, Latino, South Asian and other populations, increasing the likelihood this could be a low frequency benign variant. There is conflicting information in the literature. Two in-silico functional studies suggest this variant is predicted neutral (Easton 2007, Lindor 2012), while two others suggest the variant is likely deleterious (Karchin 2008, Kluska 2015). The p.Val2969 residue is conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) provide inconsistent predictions regarding the impact to the protein; this information is not very predictive of pathogenicity. The variant occurs outside of the splicing consensus sequence and 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. This variant is classified as a variant of uncertain significance.
Clinical Genetics Laboratory, Department of Pathology, Netherlands Cancer Institute	RCV000168609	SCV001905817	benign	not specified		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000168609	SCV001952716	benign	not specified		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000168609	SCV001971544	benign	not specified		no assertion criteria provided	clinical testing
BRCAlab, Lund University	RCV000077456	SCV004243838	benign	Breast-ovarian cancer, familial, susceptibility to, 2	2020-03-02	no assertion criteria provided	clinical testing