Submissions for variant NM_000059.4(BRCA2):c.9770_9771del (p.Lys3257fs)

dbSNP: rs1566260997

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000779931	SCV000916872	likely pathogenic	Hereditary breast ovarian cancer syndrome	2018-05-29	criteria provided, single submitter	clinical testing	Variant summary: BRCA2 c.9770_9771delAA (p.Lys3257ArgfsX2) 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., p.Arg3268fsX9 and p.Tyr3308X). The variant was absent in 277164 control chromosomes. To our knowledge, no occurrence of c.9770_9771delAA in individuals affected with Hereditary Breast and Ovarian Cancer and no experimental evidence demonstrating its impact on protein function have been reported. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as likely pathogenic.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000779931	SCV001388053	pathogenic	Hereditary breast ovarian cancer syndrome	2023-03-10	criteria provided, single submitter	clinical testing	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: 632692). This variant disrupts a region of the BRCA2 protein in which other variant(s) (p.Tyr3308*) have been determined to be pathogenic (PMID: 17026620, 18593900, 18607349, 22711857). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. This sequence change creates a premature translational stop signal (p.Lys3257Argfs*3) in the BRCA2 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 162 amino acid(s) of the BRCA2 protein. For these reasons, this variant has been classified as Pathogenic.
Ambry Genetics	RCV002370053	SCV002689430	pathogenic	Hereditary cancer-predisposing syndrome	2021-07-23	criteria provided, single submitter	clinical testing	The c.9770_9771delAA pathogenic mutation, located in coding exon 26 of the BRCA2 gene, results from a deletion of two nucleotides at nucleotide positions 9770 to 9771, causing a translational frameshift with a predicted alternate stop codon (p.K3257Rfs*3). This alteration occurs at the 3' terminus of theBRCA2 gene, is not expected to trigger nonsense-mediated mRNA decay, and only impacts the last 162 AA of the protein. However, premature stop codons are typically deleterious in nature and the impacted region is critical for protein function (Ambry internal data). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). As such, this alteration is interpreted as a disease-causing mutation.