Submissions for variant NM_000059.4(BRCA2):c.2330dup (p.Asp777fs)

dbSNP: rs80359328

Total submissions: 24

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA)	RCV000077683	SCV000300509	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2016-09-08	reviewed by expert panel	curation	Variant allele predicted to encode a truncated non-functional protein.
Michigan Medical Genetics Laboratories, University of Michigan	RCV000077683	SCV000195969	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2014-11-03	criteria provided, single submitter	clinical testing
GeneDx	RCV000160270	SCV000210721	pathogenic	not provided	2021-04-08	criteria provided, single submitter	clinical testing	Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Observed in individuals with BRCA2-related cancers (Al-Saffer 2002, Edwards 2003, Oros 2004, Claus 2005, Song 2014, George 2017, Lowery 2018); Truncating variants in this gene are considered pathogenic by a well-established clinical consortium and/or database; Not observed at a significant frequency in large population cohorts (Lek 2016); Also known as 2558insA; This variant is associated with the following publications: (PMID: 27225637, 12474142, 20736950, 12414830, 26295337, 11812938, 15382066, 16905680, 24728189, 28097235, 18182994, 29506128, 15728167, 30720243, 31948886)
Ambry Genetics	RCV000163933	SCV000214529	pathogenic	Hereditary cancer-predisposing syndrome	2021-07-08	criteria provided, single submitter	clinical testing	The c.2330dupA pathogenic mutation, located in coding exon 10 of the BRCA2 gene, results from a duplication of A at nucleotide position 2330, causing a translational frameshift with a predicted alternate stop codon (p.D777Efs*11). This mutation has been reported in multiple individuals and families affected with hereditary breast and ovarian cancer (Agoff SN et al. Am. J. Surg. Pathol., 2002 Feb;26:171-8; Al-Saffar M et al. J. Med. Genet., 2002 Nov;39:e68; Oros KK et al. Int. J. Cancer, 2004 Nov;112:411-9; Claus EB et al. JAMA, 2005 Feb;293:964-9; Alsop K et al. J Clin Oncol, 2012 Jul;30:2654-63; George A et al. Sci Rep, 2016 07;6:29506; Copson ER et al. Lancet Oncol, 2018 02;19:169-180; Lowery MA et al. J Natl Cancer Inst, 2018 10;110:1067-1074; Abe T et al. J Clin Oncol, 2019 05;37:1070-1080; Dorling et al. N Engl J Med. 2021 02;384:428-439). This mutation has also been identified in multiple patients with prostate cancer (Edwards SM et al. Am. J. Hum. Genet., 2003 Jan;72:1-12; Edwards SM et al. Br J Cancer, 2010 Sep;103:918-24; Castro E et al. J Clin Oncol, 2013 May;31:1748-57; Wu Y et al. Eur Urol Oncol, 2020 04;3:224-230). This mutation has been identified in two siblings with Fanconi Anemia confirmed in trans with a different BRCA2 alteration (Rickman KA et al. Genes Dev, 2020 06;34:832-846). Of note, this alteration is also designated as 2558insA in published literature. In addition to the clinical data presented in the literature, this alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000206474	SCV000259811	pathogenic	Hereditary breast ovarian cancer syndrome	2024-01-02	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Asp777Glufs*11) in the BRCA2 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in BRCA2 are known to be pathogenic (PMID: 20104584). This variant is present in population databases (rs80359328, gnomAD 0.0009%). This premature translational stop signal has been observed in individual(s) with prostate cancer (PMID: 11812938, 12414830, 12474142, 24728189). This variant is also known as 2558insA. ClinVar contains an entry for this variant (Variation ID: 91775). For these reasons, this variant has been classified as Pathogenic.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000160270	SCV000296622	pathogenic	not provided	2020-01-24	criteria provided, single submitter	clinical testing	The variant results in a shift of the reading frame, and is therefore predicted to result in the loss of a functional protein. Found in at least one patient with expected phenotype for this gene, and found in general population data at a frequency that is consistent with pathogenicity.
Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge	RCV000077683	SCV000326691	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2015-10-02	criteria provided, single submitter	clinical testing
Department of Pathology and Molecular Medicine, Queen's University	RCV000206474	SCV000588083	pathogenic	Hereditary breast ovarian cancer syndrome	2017-04-20	criteria provided, single submitter	clinical testing
Counsyl	RCV000077683	SCV000677671	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2017-04-14	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000163933	SCV000683480	pathogenic	Hereditary cancer-predisposing syndrome	2023-08-04	criteria provided, single submitter	clinical testing	This variant inserts 1 nucleotide in exon 11 of the BRCA2 gene, creating a frameshift and premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. This variant has been reported in individuals affected with breast, ovarian, pancreatic, and prostate cancer (PMID: 11812938, 15382066, 20736950, 22711857, 24728189, 27406733, 29337092, 29506128). In a large breast cancer case-control study conducted by the BRIDGES consortium, this variant was reported in 1/60466 cases and 3/53461 unaffected controls (PMID: 33471991; Leiden Open Variation Database DB-ID BRCA2_002354). This variant has also been reported in two sibling affected with Fanconi anemia, in trans with a second BRCA2 variant (PMID: 32354836). This variant has been identified in 1/250952 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Loss of BRCA2 function is a known mechanism of disease (clinicalgenome.org). Based on the available evidence, this variant is classified as Pathogenic.
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV000735532	SCV000902194	pathogenic	Breast and/or ovarian cancer	2023-05-19	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000206474	SCV000919031	pathogenic	Hereditary breast ovarian cancer syndrome	2018-12-04	criteria provided, single submitter	clinical testing	Variant summary: BRCA2 c.2330dupA (p.Asp777GlufsX11) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have been classified as pathogenic by our laboratory (eg. c.2368G>T/p.Glu790X, c.2400_2401delTA/p.Asn801fsX3). The variant allele was found at a frequency of 8e-06 in 248882 control chromosomes (gnomAD and publication data). c.2330dupA has been reported in the literature in multiple individuals affected with Hereditary Breast and Ovarian Cancer and other tumor phenotypes. These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported (Edwards_2003, Oros_2004, Alsop_2012, Song_2014, George_2016). Nine clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Sema4, Sema4	RCV000163933	SCV002533309	pathogenic	Hereditary cancer-predisposing syndrome	2022-01-25	criteria provided, single submitter	curation
Genetics and Molecular Pathology, SA Pathology	RCV002272056	SCV002556760	pathogenic	Familial cancer of breast	2020-10-28	criteria provided, single submitter	clinical testing	The BRCA2 c.2330dupA variant is classified as Pathogenic (PVS1, PM2, PP5)
Revvity Omics, Revvity	RCV000160270	SCV003816090	pathogenic	not provided	2022-07-08	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV002272056	SCV004211919	pathogenic	Familial cancer of breast	2023-11-04	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV000077683	SCV004847040	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2023-11-07	criteria provided, single submitter	clinical testing	This variant inserts 1 nucleotide in exon 11 of the BRCA2 gene, creating a frameshift and premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. This variant has been reported in individuals affected with breast, ovarian, pancreatic, and prostate cancer (PMID: 11812938, 15382066, 20736950, 22711857, 24728189, 27406733, 29337092, 29506128). In a large breast cancer case-control study conducted by the BRIDGES consortium, this variant was reported in 1/60466 cases and 3/53461 unaffected controls (PMID: 33471991; Leiden Open Variation Database DB-ID BRCA2_002354). This variant has also been reported in two sibling affected with Fanconi anemia, in trans with a second BRCA2 variant (PMID: 32354836). This variant has been identified in 1/250952 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Loss of BRCA2 function is a known mechanism of disease (clinicalgenome.org). Based on the available evidence, this variant is classified as Pathogenic.
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000206474	SCV004847917	pathogenic	Hereditary breast ovarian cancer syndrome	2019-10-14	criteria provided, single submitter	clinical testing	The p.Asp777GlufsX11 variant in BRCA2 has been reported in >15 individuals with BRCA2-related cancers (Agoff 2002, Edwards 2003, Lowery 2018, Castro 2013, Alsop 2012, Oros 2006, BIC database). It has also been identified in 1/113388 European chromosomes by gnomAD (http://gnomad.broadinstitute.org); however, this frequency is low enough to be consistent with the frequency of hereditary breast and ovarian cancer (HBOC) in the general population. This variant is predicted to cause a frameshift, which alters the protein’s amino acid sequence beginning at position 777 and leads to a premature termination codon 11 amino acids downstream. This alteration is then predicted to lead to a truncated or absent protein. Loss of function of the BRCA2 gene is an established disease mechanism in autosomal dominant hereditary breast and ovarian cancer syndrome (HBOC). Additionally, this variant was classified as Pathogenic on Sept 8 2016 by the ClinGen-approved ENIGMA expert panel (Variation ID: 91775). In summary, this variant meets criteria to be classified as pathogenic for autosomal dominant HBOC. ACMG/AMP Criteria applied: PVS1, PM2, PS4.
OMIM	RCV000009928	SCV000030149	pathogenic	Malignant tumor of prostate	2003-01-01	no assertion criteria provided	literature only
Sharing Clinical Reports Project (SCRP)	RCV000077683	SCV000109486	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2011-12-12	no assertion criteria provided	clinical testing
Breast Cancer Information Core (BIC) (BRCA2)	RCV000077683	SCV000146031	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2002-05-29	no assertion criteria provided	clinical testing
Research Molecular Genetics Laboratory, Women's College Hospital, University of Toronto	RCV000206474	SCV000587629	pathogenic	Hereditary breast ovarian cancer syndrome	2014-01-31	no assertion criteria provided	research
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001353737	SCV000591801	pathogenic	Malignant tumor of breast		no assertion criteria provided	clinical testing	The p.Asp777GlufsX11 duplication variant was identified in 3 of 1790 proband chromosomes (frequency 0.002) from individuals with breast cancer, ovarian cancer, fallopian tube carcinoma, or prostate cancer (Agoff 2002, Claus 2005, Edwards 2010). The variant was also identified in dbSNP (ID: rs80359328) “With pathogenic allele”, HGMD, LOVD, UMD (2X as a causal variant), and the BIC database (10X with clinical importance). The p.Asp777GlufsX11 duplication variant is predicted to cause a frameshift, which alters the protein's amino acid sequence beginning at codon 777 and leads to a premature stop codon 11 codons downstream. This alteration is then predicted to result in a truncated or absent protein and loss of function. Loss of function variants of the BRCA2 gene are an established mechanism of disease in hereditary breast and ovarian cancer and is the type of variant expected to cause the disorder. In summary, based on the above information, this variant meets our laboratory’s criteria to be classified as pathogenic.
Foulkes Cancer Genetics LDI, Lady Davis Institute for Medical Research	RCV000735532	SCV000863670	pathogenic	Breast and/or ovarian cancer	2015-10-28	no assertion criteria provided	clinical testing