Submissions for variant NM_000059.4(BRCA2):c.3172A>T (p.Lys1058Ter)

dbSNP: rs730881521

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA)	RCV000162052	SCV000300593	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.
GeneDx	RCV000160058	SCV000210307	pathogenic	not provided	2019-09-04	criteria provided, single submitter	clinical testing	Nonsense 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 2016); Variant observed in breast and ovarian cancer families (Tea 2014, Rebbeck 2018); Truncating variants in this gene are considered pathogenic by a well-established clinical consortium and/or database; Also known as 3400A>T; This variant is associated with the following publications: (PMID: 24156927, 29446198)
Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge	RCV000162052	SCV000326829	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2015-10-02	criteria provided, single submitter	clinical testing
Invitae	RCV000467920	SCV000549658	pathogenic	Hereditary breast ovarian cancer syndrome	2023-12-12	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Lys1058*) 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 a personal and/or family history of breast and/or ovarian cancer (PMID: 24156927, 26681312, 29446198). ClinVar contains an entry for this variant (Variation ID: 182196). For these reasons, this variant has been classified as Pathogenic.
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000467920	SCV000605798	pathogenic	Hereditary breast ovarian cancer syndrome	2016-08-15	criteria provided, single submitter	clinical testing	The p.Lys1058X variant in BRCA2 has been reported in 1 individual with a persona l or familial history of BRCA2-associated cancer (Tea 2014) and was absent from large population studies. This nonsense variant leads to a premature termination codon at position 1058, which is predicted to lead to a truncated or absent pro tein. Heterozygous loss of function of the BRCA2 gene is an established disease mechanism in hereditary breast and ovarian cancer (HBOC). In addition, this vari ant was classified as Pathogenic on Sep 8, 2016 by the ClinGen-approved ENIGMA e xpert panel (ClinVar SCV000300593). In summary, this variant meets criteria to b e classified as pathogenic for HBOC in an autosomal dominant manner based upon t he predicted impact to the protein.
Equipe Genetique des Anomalies du Developpement, Université de Bourgogne	RCV000162052	SCV001190271	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2019-06-04	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002321671	SCV002610052	pathogenic	Hereditary cancer-predisposing syndrome	2018-04-09	criteria provided, single submitter	clinical testing	The p.K1058* pathogenic mutation (also known as c.3172A>T), located in coding exon 10 of the BRCA2 gene, results from an A to T substitution at nucleotide position 3172. This changes the amino acid from a lysine to a stop codon within coding exon 10. This mutation was previously identified in one individual of Austrian descent with personal and/or family history of breast and/or ovarian cancer (Tea MK, Maturitas 2014 Jan; 77(1):68-72). 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.
Institute of Human Genetics, Medical University Innsbruck	RCV000162052	SCV000212015	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2015-02-11	no assertion criteria provided	clinical testing
BRCAlab, Lund University	RCV000162052	SCV004243600	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2020-03-02	no assertion criteria provided	clinical testing