Submissions for variant NM_000059.4(BRCA2):c.26del (p.Pro9fs)

dbSNP: rs80359343

Total submissions: 17

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA)	RCV000077284	SCV000282371	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2016-04-22	reviewed by expert panel	curation	Variant allele predicted to encode a truncated non-functional protein.
Invitae	RCV000044041	SCV000072054	pathogenic	Hereditary breast ovarian cancer syndrome	2023-12-15	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Pro9Glnfs*16) 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 not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with hereditary breast and ovarian cancer (PMID: 8988179, 11044354, 17636422, 22711857, 23028338). It has also been observed to segregate with disease in related individuals. This variant is also known as 253delC. ClinVar contains an entry for this variant (Variation ID: 51330). For these reasons, this variant has been classified as Pathogenic.
Ambry Genetics	RCV000132408	SCV000187500	pathogenic	Hereditary cancer-predisposing syndrome	2022-09-06	criteria provided, single submitter	clinical testing	The c.26delC pathogenic mutation, located in coding exon 1 of the BRCA2 gene, results from a deletion of one nucleotide at position 26, causing a translational frameshift with a predicted alternate stop codon (p.P9Qfs*16). This mutation has been identified in multiple individuals with breast, ovarian, prostate, and/or pancreatic cancers (Gayther SA et al. Nat. Genet. 1997 Jan;15(1):103-5; Evans DG et al. Fam. Cancer 2008 Jul;7(2):113-7; Alsop K et al. J. Clin. Oncol. 2012 Jul;30(21):2654-63; Thompson ER et al. PLoS Genet. 2012 Sep;8(9):e1002894; Pritchard CC et al. N. Engl. J. Med. 2016 Aug 4;375(5):443-53; Schenkel LC et al. J. Mol. Diagn. 2016 09;18(5):657-667; Hu C et al. JAMA 2018 06;319(23):2401-2409). This alteration was identified in a large, worldwide study of BRCA1/2 mutation positive families (Rebbeck TR et al. Hum. Mutat. 2018 05;39(5):593-620). Of note, this alteration is also designated as 254delC and 253delC 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.
GeneDx	RCV000215325	SCV000278834	pathogenic	not provided	2023-06-01	criteria provided, single submitter	clinical testing	Observed in individuals with a personal or family history consistent with pathogenic variants in this gene (Gayther et al., 1997; Basham et al., 2002; Evans et al., 2008; Tutt et al., 2010; Alsop et al., 2012; Thompson et al., 2012; Frugtniet et al., 2022); 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; Truncating variants in this gene are considered pathogenic by a well-established clinical consortium and/or database; Not observed at significant frequency in large population cohorts (gnomAD); Also known as 252delC, 253delC, and 254delC; This variant is associated with the following publications: (PMID: 22711857, 21702907, 14662532, 15131399, 31263054, 8988179, 12036913, 27376475, 23028338, 11879560, 20609467, 17636422, 11044354, 18158280, 27433846, 30787465, 28888541, 32778766, 29922827, 33758026, 34657373)
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000077284	SCV000296580	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2015-12-30	criteria provided, single submitter	clinical testing
Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge	RCV000077284	SCV000326745	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2015-10-02	criteria provided, single submitter	clinical testing
Counsyl	RCV000077284	SCV000489184	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2016-08-31	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000044041	SCV000694620	pathogenic	Hereditary breast ovarian cancer syndrome	2021-04-23	criteria provided, single submitter	clinical testing	Variant summary: BRCA2 c.26delC (p.Pro9GlnfsX16) 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. The variant was absent in 251392 control chromosomes. c.26delC has been widely reported in the literature in multiple individuals affected with Hereditary Breast And Ovarian Cancer Syndrome (example, Rebbeck_2018). 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. Multiple clinical diagnostic laboratories, an expert panel (ENIGMA) and a consortium (CIMBA) have submitted clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Color Diagnostics, LLC DBA Color Health	RCV000132408	SCV001350920	pathogenic	Hereditary cancer-predisposing syndrome	2020-01-15	criteria provided, single submitter	clinical testing	This variant deletes 1 nucleotide in exon 2 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 not been identified 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.
Revvity Omics, Revvity	RCV000215325	SCV002020244	pathogenic	not provided	2019-06-12	criteria provided, single submitter	clinical testing
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV001798229	SCV002042536	pathogenic	Breast and/or ovarian cancer	2019-08-21	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000132408	SCV002535517	pathogenic	Hereditary cancer-predisposing syndrome	2021-09-02	criteria provided, single submitter	curation
Sharing Clinical Reports Project (SCRP)	RCV000077284	SCV000109081	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2007-02-15	no assertion criteria provided	clinical testing
Breast Cancer Information Core (BIC) (BRCA2)	RCV000077284	SCV000146029	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2004-02-20	no assertion criteria provided	clinical testing
Research Molecular Genetics Laboratory, Women's College Hospital, University of Toronto	RCV000044041	SCV000587527	pathogenic	Hereditary breast ovarian cancer syndrome	2014-01-31	no assertion criteria provided	research
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001353718	SCV000591654	pathogenic	Malignant tumor of breast		no assertion criteria provided	clinical testing	The p.Pro9GlnfsX16 deletion variant was identified in 4 of 3028 proband chromosomes (frequency: 0.001) from individuals or families with breast or ovarian cancer (Alsop 2012, Gayther 1997, Weitzel 2003).The variant was also identified in dbSNP (ID: rs80359343) “With pathogenic allele”, HGMD, LOVD, UMD (1X as a causal variant), and the BIC database (7X as clinically important). The p.Pro9GlnfsX16 deletion variant is predicted to cause a frameshift, which alters the protein's amino acid sequence beginning at codon 9 and leads to a premature stop codon 16 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.
BRCAlab, Lund University	RCV000077284	SCV004244036	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2020-03-02	no assertion criteria provided	clinical testing