Submissions for variant NM_000059.4(BRCA2):c.2380dup (p.Met794fs)

dbSNP: rs730881602

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA)	RCV000238934	SCV000300515	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.
GeneDx	RCV000160271	SCV000210722	pathogenic	not provided	2014-09-16	criteria provided, single submitter	clinical testing	This duplication of one nucleotide in BRCA2 is denoted c.2380dupA at the cDNA level and p.Met794AsnfsX8 (M794NfsX8) at the protein level. The normal sequence, with the bases that are duplicated in brackets, is CAAA[A]TGTC. The duplication causes a frameshift, which changes a Methionine to an Asparagine at codon 794, and creates a premature stop codon at position 8 of the new reading frame. Although this variant has not, to our knowledge, been reported in the literature, it is predicted to cause loss of normal protein function through either protein truncation or nonsense-mediated mRNA decay. we consider this variant to be pathogenic.
Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge	RCV000238934	SCV000326695	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2015-10-02	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000496543	SCV000635217	pathogenic	Hereditary breast ovarian cancer syndrome	2024-01-10	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Met794Asnfs*8) 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 high risk of breast and/or ovarian cancer (PMID: 29446198). ClinVar contains an entry for this variant (Variation ID: 182309). For these reasons, this variant has been classified as Pathogenic.
Ambry Genetics	RCV000570975	SCV000666038	pathogenic	Hereditary cancer-predisposing syndrome	2022-06-28	criteria provided, single submitter	clinical testing	The c.2380dupA pathogenic mutation, located in coding exon 10 of the BRCA2 gene, results from a duplication of A at nucleotide position 2380, causing a translational frameshift with a predicted alternate stop codon (p.M794Nfs*8). 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.
Counsyl	RCV000238934	SCV000677805	likely pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2016-12-28	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV003474826	SCV004210529	pathogenic	Familial cancer of breast	2022-07-25	criteria provided, single submitter	clinical testing
Sharing Clinical Reports Project (SCRP)	RCV000238934	SCV000297510	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2013-11-05	no assertion criteria provided	clinical testing
Research Molecular Genetics Laboratory, Women's College Hospital, University of Toronto	RCV000496543	SCV000587630	pathogenic	Hereditary breast ovarian cancer syndrome	2014-01-31	no assertion criteria provided	research
PreventionGenetics, part of Exact Sciences	RCV004724947	SCV005338816	pathogenic	BRCA2-related disorder	2024-09-17	no assertion criteria provided	clinical testing	The BRCA2 c.2380dupA variant is predicted to result in a frameshift and premature protein termination (p.Met794Asnfs*8). This variant was reported in individuals with a personal and/or family history of breast and/or ovarian cancer (Table S2, Guindalini et al. 2019. PubMed ID: 30154229; Supplementary Table 1, Rebbeck et al. 2018. PubMed ID: 29446198). This variant has not been reported in a large population database, indicating this variant is rare. Frameshift variants in BRCA2 are expected to be pathogenic. This variant is interpreted as pathogenic.