Submissions for variant NM_000059.4(BRCA2):c.407del (p.Asn136fs)

dbSNP: rs80359425

Total submissions: 15

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA)	RCV000031457	SCV000300319	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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000044342	SCV000072355	pathogenic	Hereditary breast ovarian cancer syndrome	2024-11-17	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Asn136Ilefs*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 variant has not been reported in the literature in individuals affected with BRCA2-related conditions. ClinVar contains an entry for this variant (Variation ID: 37876). For these reasons, this variant has been classified as Pathogenic.
Ambry Genetics	RCV000131981	SCV000187039	pathogenic	Hereditary cancer-predisposing syndrome	2022-04-18	criteria provided, single submitter	clinical testing	The c.407delA pathogenic mutation, located in coding exon 3 of the BRCA2 gene, results from a deletion of one nucleotide at nucleotide position 407, causing a translational frameshift with a predicted alternate stop codon (p.N136Ifs*16). In a large, clinic-based BRCA1/2 testing cohort in Norway, this variant was detected in one family (Heramb C et al. Hered Cancer Clin Pract. 2018 Jan;16:3). 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.
Michigan Medical Genetics Laboratories, University of Michigan	RCV000031457	SCV000267728	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2016-04-21	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000255242	SCV000296688	pathogenic	not provided	2024-09-04	criteria provided, single submitter	clinical testing	The BRCA2 c.407del (p.Asn136Ilefs*16) variant alters the translational reading frame of the BRCA2 mRNA and causes the premature termination of BRCA2 protein synthesis. This variant has been reported in the published literature in an individual affected with breast cancer whose tumor showed loss of heterozygosity (LOH) (PMID: 26556299 (2016)). It was also briefly reported in other individuals/families (PMIDs: 29339979 (2018), 32614418 (2020)). Functional studies indicate that this variant does not produce full length transcript and produces only alternative isoforms with residual activity (PMIDs: 28765325 (2017), 32393813 (2020)). This variant has not been reported in large, multi-ethnic general populations (Genome Aggregation Database, http://gnomad.broadinstitute.org). Based on the available information, this variant is classified as pathogenic.
GeneDx	RCV000255242	SCV000321444	pathogenic	not provided	2023-04-25	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 a personal or family history consistent with pathogenic variants in this gene (Schrader et al., 2016; Mutter et al., 2017; Frugtniet et al., 2022); Published functional studies demonstrate a damaging effect: failed to rescue susceptibility to DNA damaging agents (Stauffer et al., 2020); Not observed at significant frequency in large population cohorts (gnomAD); Truncating variants in this gene are considered pathogenic by a well-established clinical consortium and/or database; Also known as 635delA; This variant is associated with the following publications: (PMID: 28299801, 29339979, 29446198, 28765325, 26556299, 30787465, 31948886, 32393813, 28888541, 34657373)
Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge	RCV000031457	SCV000326967	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2015-10-02	criteria provided, single submitter	clinical testing
Department of Medical Genetics, Oslo University Hospital	RCV000031457	SCV000605660	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2015-07-01	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000131981	SCV000903713	pathogenic	Hereditary cancer-predisposing syndrome	2022-03-17	criteria provided, single submitter	clinical testing	This variant deletes 1 nucleotide in exon 4 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 3 individuals affected with breast cancer (PMID: 26556299, 28765325, 33471991; Leiden Open Variation Database DB-ID BRCA2_004046) and has been identified in 7 families among the CIMBA participants (PMID: 29446198). 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000044342	SCV000918833	pathogenic	Hereditary breast ovarian cancer syndrome	2020-11-12	criteria provided, single submitter	clinical testing	Variant summary: BRCA2 c.407delA (p.Asn136IlefsX16) 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 250874 control chromosomes (gnomAD). c.407delA has been reported in the literature in multiple individuals affected with Hereditary Breast And Ovarian Cancer Syndrome (Schrader_2016, Mutter_2017, Weigelt_2017, Heramb_2018, Rebbeck_2018, BIC_database). These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function, demonstrating truncated/absent protein and loss of interaction with PALB2 and RAD51 (Weigelt_2017). Nine ClinVar submitters (evaluation after 2014) cite the variant as pathogenic, including one expert panel (ENIGMA). Based on the evidence outlined above, the variant was classified as pathogenic.
Revvity Omics, Revvity	RCV000255242	SCV003811865	pathogenic	not provided	2022-12-07	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV003460509	SCV004216054	pathogenic	Familial cancer of breast	2023-06-30	criteria provided, single submitter	clinical testing
Sharing Clinical Reports Project (SCRP)	RCV000031457	SCV000054062	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2012-04-12	no assertion criteria provided	clinical testing
Breast Cancer Information Core (BIC) (BRCA2)	RCV000031457	SCV000146777	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	RCV000044342	SCV000587546	pathogenic	Hereditary breast ovarian cancer syndrome	2014-01-31	no assertion criteria provided	research