Submissions for variant NM_000059.4(BRCA2):c.1277A>C (p.Lys426Thr)

dbSNP: rs1421854019

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000568483	SCV000661321	uncertain significance	Hereditary cancer-predisposing syndrome	2024-05-09	criteria provided, single submitter	clinical testing	The p.K426T variant (also known as c.1277A>C), located in coding exon 9 of the BRCA2 gene, results from an A to C substitution at nucleotide position 1277. The lysine at codon 426 is replaced by threonine, an amino acid with similar properties. This amino acid position is not well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Based on the available evidence, the clinical significance of this variant remains unclear.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000588909	SCV000694528	uncertain significance	not provided	2017-08-21	criteria provided, single submitter	clinical testing	Variant summary: The BRCA2 c.1277A>C (p.Lys426Thr) variant involves the alteration of a conserved nucleotide. 4/5 in silico tools predict damaging outcome for this variant. This variant is absent in 120474 control chromosomes from ExAC. This variant has been found in one breast cancer patient who had positive family history (Solano_2016), however without strong evidence for or against pathogenicity. There are no functional studies published for this variant. Taken together, this variant is classified as Variant of Unknown Significance.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000637322	SCV000758773	uncertain significance	Hereditary breast ovarian cancer syndrome	2022-10-13	criteria provided, single submitter	clinical testing	This sequence change replaces lysine, which is basic and polar, with threonine, which is neutral and polar, at codon 426 of the BRCA2 protein (p.Lys426Thr). This variant is present in population databases (no rsID available, gnomAD 0.0009%). This missense change has been observed in individual(s) with clinical features of BRCA2-related conditions (PMID: 21520333). ClinVar contains an entry for this variant (Variation ID: 479333). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt BRCA2 protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
University of Washington Department of Laboratory Medicine, University of Washington	RCV000568483	SCV003849957	likely benign	Hereditary cancer-predisposing syndrome	2023-03-23	criteria provided, single submitter	curation	Missense variant in a coldspot region where missense variants are very unlikely to be pathogenic (PMID:31911673).
Color Diagnostics, LLC DBA Color Health	RCV000568483	SCV004361221	uncertain significance	Hereditary cancer-predisposing syndrome	2022-04-05	criteria provided, single submitter	clinical testing	This missense variant replaces lysine with threonine at codon 426 of the BRCA2 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in 1 individual affected with early-onset breast cancer (PMID: 28947987). This variant has been identified in 1/243758 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
GeneDx	RCV000588909	SCV005079974	uncertain significance	not provided	2024-01-24	criteria provided, single submitter	clinical testing	Observed in a patient with breast cancer (PMID: 28947987); In silico analysis supports that this missense variant does not alter protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); Also known as 1505A>C; This variant is associated with the following publications: (PMID: Samtani2019[CaseReport], 28947987)
Molecular Diagnostics Laboratory, Catalan Institute of Oncology	RCV000568483	SCV005902356	likely benign	Hereditary cancer-predisposing syndrome	2024-09-18	criteria provided, single submitter	clinical testing	BP1_Strong c.1277A>C, located in exon 10 of the BRCA2 gene, is predicted to result in the substitution of lysine by threonine at codon 426, p.(Lys426Thr). This position is outside a (potentially) clinically important functional domain and, moreover, the SpliceAI algorithm predicts no significant impact on splicing (BP1_strong). This variant is found in 1/260642 alleles at a frequency of 0.0004% in the gnomAD v2.1.1 database, non-cancer dataset. To our knowledge, no well-established functional studies have been reported for this variant. It has been reported in patients with BRCA-related conditions (PMID: 28947987, 31853058 and data from our internal cohort of patients). This variant has been reported in the ClinVar database (5x uncertain significance, 1x benign), in the LOVD database (2x uncertain significance) and in BRCA Exchange database (where it has not been reviewed yet). Based on currently available information, the variant c.1277A>C should be considered a likely benign variant.