Submissions for variant NM_000059.4(BRCA2):c.6331_6332del (p.Lys2111fs)

dbSNP: rs587781470

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA)	RCV000225411	SCV000282423	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.
Ambry Genetics	RCV000129412	SCV000184182	pathogenic	Hereditary cancer-predisposing syndrome	2024-08-30	criteria provided, single submitter	clinical testing	The c.6331_6332delAA pathogenic mutation, located in coding exon 10 of the BRCA2 gene, results from a deletion of two nucleotides at nucleotide positions 6331 to 6332, causing a translational frameshift with a predicted alternate stop codon (p.K2111Efs*17). This mutation has been detected in multiple breast cancer cohorts (Rummel SK et al. Breast Cancer Res Treat. 2017 Aug;164:593-601; Rebbeck TR et al. Hum Mutat. 2018 05;39:593-620; Nones K et al. Ann Oncol. 2019 07;30:1071-1079). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). 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.
Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge	RCV000225411	SCV000327396	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2015-10-02	criteria provided, single submitter	clinical testing
GeneDx	RCV000484123	SCV000567724	pathogenic	not provided	2019-07-02	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; Not observed in large population cohorts (Lek et al., 2016); This variant is associated with the following publications: (PMID: 28503720, 28152038, 31090900, 32719484)
Labcorp Genetics (formerly Invitae), Labcorp	RCV000698191	SCV000826840	pathogenic	Hereditary breast ovarian cancer syndrome	2024-09-28	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Lys2111Glufs*17) 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 breast cancer (PMID: 28503720). ClinVar contains an entry for this variant (Variation ID: 141068). For these reasons, this variant has been classified as Pathogenic.
Color Diagnostics, LLC DBA Color Health	RCV000129412	SCV002052057	pathogenic	Hereditary cancer-predisposing syndrome	2021-02-01	criteria provided, single submitter	clinical testing	This variant deletes 2 nucleotides 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. To our knowledge, functional studies have not been reported for this variant. This variant has been reported in individuals affected with breast cancer (PMID: 28503720) or suspected of having hereditary breast/ovarian cancer (PMID: 30055349). 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	RCV000698191	SCV002599057	pathogenic	Hereditary breast ovarian cancer syndrome	2022-09-15	criteria provided, single submitter	clinical testing	Variant summary: BRCA2 c.6331_6332delAA (p.Lys2111GlufsX17) 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 245118 control chromosomes. c.6331_6332delAA has been reported in the literature in individuals affected with Hereditary Breast and Ovarian Cancer Syndrome (e.g. Rummel_2017, Nones_2019, Sokolenko_2020). These data indicate that the variant is likely to be associated with disease. Six 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.
Baylor Genetics	RCV003474747	SCV004212900	pathogenic	Familial cancer of breast	2024-02-02	criteria provided, single submitter	clinical testing