Submissions for variant NM_000059.4(BRCA2):c.1819A>T (p.Lys607Ter)

dbSNP: rs80358471

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)	RCV000077668	SCV000300465	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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000496499	SCV002231920	pathogenic	Hereditary breast ovarian cancer syndrome	2021-09-17	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Pathogenic. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. ClinVar contains an entry for this variant (Variation ID: 91760). This variant has not been reported in the literature in individuals affected with BRCA2-related conditions. This variant is not present in population databases (ExAC no frequency). This sequence change creates a premature translational stop signal (p.Lys607*) 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).
Ambry Genetics	RCV002408604	SCV002712020	pathogenic	Hereditary cancer-predisposing syndrome	2020-06-30	criteria provided, single submitter	clinical testing	The p.K607* pathogenic mutation (also known as c.1819A>T), located in coding exon 9 of the BRCA2 gene, results from an A to T substitution at nucleotide position 1819. This changes the amino acid from a lysine to a stop codon within coding exon 9. This alteration was identified in a large, worldwide study of BRCA1/2 mutation positive families (Rebbeck TR et al. Hum Mutat. 2018 May;39(5):593-620). 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000496499	SCV003929379	pathogenic	Hereditary breast ovarian cancer syndrome	2023-04-14	criteria provided, single submitter	clinical testing	Variant summary: BRCA2 c.1819A>T (p.Lys607X) 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 240812 control chromosomes. c.1819A>T has been reported in individuals affected with Hereditary Breast And Ovarian Cancer Syndrome (Bilyalov_2022, BIC database). Three submitters, including an expert panel (ENIGMA), have provided clinical-significance assessments for this variant to ClinVar after 2014, and classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Clinical Genetics Laboratory, Skane University Hospital Lund	RCV004696693	SCV005199776	pathogenic	not provided	2023-06-27	criteria provided, single submitter	clinical testing
Sharing Clinical Reports Project (SCRP)	RCV000077668	SCV000109471	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2012-05-01	no assertion criteria provided	clinical testing
Breast Cancer Information Core (BIC) (BRCA2)	RCV000077668	SCV000145957	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2002-05-29	no assertion criteria provided	clinical testing
Research Molecular Genetics Laboratory, Women's College Hospital, University of Toronto	RCV000496499	SCV000587616	pathogenic	Hereditary breast ovarian cancer syndrome	2014-01-31	no assertion criteria provided	research