Submissions for variant NM_000059.4(BRCA2):c.4591A>T (p.Lys1531Ter)

dbSNP: rs1555283865

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000557526	SCV000635387	pathogenic	Hereditary breast ovarian cancer syndrome	2017-03-12	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Pathogenic. While this particular variant has not been reported in the literature, loss-of-function variants in BRCA2 are known to be pathogenic (PMID: 20104584). This sequence change creates a premature translational stop signal at codon 1531 (p.Lys1531*) of the BRCA2 gene. It is expected to result in an absent or disrupted protein product.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000557526	SCV000694786	likely pathogenic	Hereditary breast ovarian cancer syndrome	2017-06-29	criteria provided, single submitter	clinical testing	Variant summary: The BRCA2 c.4591A>T (p.Lys1531X) variant results in a premature termination codon, predicted to cause a truncated or absent BRCA2 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 (e.g.c.7757G>A/p.Trp2586X, c.8575delC/p.Gln2859fsX4). One in silico tool predicts a damaging outcome for this variant. This variant is absent in 120446 control chromosomes. The variant of interest has not, to our knowledge, been reported in affected individuals via publications and/or reputable databases/clinical diagnostic laboratories; nor evaluated for functional impact by in vivo/vitro studies. Taken together, this variant is classified as likely pathogenic.
GeneDx	RCV000657707	SCV000779456	pathogenic	not provided	2017-01-17	criteria provided, single submitter	clinical testing	This variant is denoted BRCA2 c.4591A>T at the cDNA level and p.Lys1531Ter (K1531X) at the protein level. The substitution creates a nonsense variant, which changes a Lysine to a premature stop codon (AAA>TAA), and is predicted to cause loss of normal protein function through either protein truncation or nonsense-mediated mRNA decay. Using alternate nomenclature, this variant would be defined as BRCA2 c.4819A>T. Although this variant has not, to our knowledge, been reported in the literature, it is considered pathogenic.
Ambry Genetics	RCV001022751	SCV001184521	pathogenic	Hereditary cancer-predisposing syndrome	2018-04-26	criteria provided, single submitter	clinical testing	The p.K1531* pathogenic mutation (also known as c.4591A>T), located in coding exon 10 of the BRCA2 gene, results from an A to T substitution at nucleotide position 4591. This changes the amino acid from a lysine to a stop codon within coding exon 10. 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.