Submissions for variant NM_000059.4(BRCA2):c.4312_4313dup (p.Ala1439fs)

dbSNP: rs1064794168

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA)	RCV000661660	SCV000783962	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2017-12-15	reviewed by expert panel	curation	Variant allele predicted to encode a truncated non-functional protein.
GeneDx	RCV000485373	SCV000568045	pathogenic	not provided	2015-09-22	criteria provided, single submitter	clinical testing	This duplication of 2 nucleotides in BRCA2 is denoted c.4312_4313dupGT at the cDNA level and p.Ala1439SerfsX10 (A1439SfsX10) at the protein level. The normal sequence, with the bases that are duplicated in braces, is TAGT[GT]CGCC. The duplication causes a frameshift, which changes an Alanine to a Serine at codon 1439, and creates a premature stop codon at position 10 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.
Invitae	RCV000542015	SCV000635356	pathogenic	Hereditary breast ovarian cancer syndrome	2023-05-19	criteria provided, single submitter	clinical testing	This variant is not present in population databases (gnomAD no frequency). For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 419879). This variant has not been reported in the literature in individuals affected with BRCA2-related conditions. This sequence change creates a premature translational stop signal (p.Ala1439Serfs*10) 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).
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000542015	SCV001339003	likely pathogenic	Hereditary breast ovarian cancer syndrome	2020-03-13	criteria provided, single submitter	clinical testing	Variant summary: BRCA2 c.4312_4313dupGT (p.Ala1439SerfsX10) 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 243748 control chromosomes. To our knowledge, no occurrence of c.4312_4313dupGT in individuals affected with Hereditary Breast and Ovarian Cancer and no experimental evidence demonstrating its impact on protein function have been reported. Three 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 likely pathogenic.
Color Diagnostics, LLC DBA Color Health	RCV001525069	SCV001735077	pathogenic	Hereditary cancer-predisposing syndrome	2020-07-27	criteria provided, single submitter	clinical testing	This variant inserts 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, this variant has not been reported in individuals affected with hereditary cancer in the literature. 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.