Submissions for variant NM_000059.4(BRCA2):c.6923A>C (p.Lys2308Thr)

dbSNP: rs186810431

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000759651	SCV000570311	uncertain significance	not provided	2016-05-11	criteria provided, single submitter	clinical testing	This variant is denoted BRCA2 c.6923A>C at the cDNA level, p.Lys2308Thr (K2308T) at the protein level, and results in the change of a Lysine to a Threonine (AAA>ACA). Using alternate nomenclature, this variant would be defined as BRCA2 7151A>C. This variant has not, to our knowledge, been published in the literature as pathogenic or benign. BRCA2 Lys2308Thr was not observed at significant allele frequency in the 1000 Genomes Project. Since Lysine and Threonine differ in some properties, this is considered a semi-conservative amino acid substitution. BRCA2 Lys2308Thr occurs at a position where amino acids with properties similar to Lysine are tolerated across species and is not located in a known functional domain. In silico analyses are inconsistent regarding the effect this variant may have on protein structure and function. Based on currently available evidence, it is unclear whether BRCA2 Lys2308Thr is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Ambry Genetics	RCV000567072	SCV000668751	uncertain significance	Hereditary cancer-predisposing syndrome	2024-12-04	criteria provided, single submitter	clinical testing	The p.K2308T variant (also known as c.6923A>C), located in coding exon 11 of the BRCA2 gene, results from an A to C substitution at nucleotide position 6923. The lysine at codon 2308 is replaced by threonine, an amino acid with similar properties. This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000759651	SCV000889115	uncertain significance	not provided	2021-07-01	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000567072	SCV001341959	uncertain significance	Hereditary cancer-predisposing syndrome	2019-10-09	criteria provided, single submitter	clinical testing	This missense variant replaces lysine with threonine at codon 2308 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). Splice site prediction tools suggest that this variant may not impact RNA splicing. To our knowledge, functional studies have not been performed for this variant. This variant has not been reported in individuals affected with hereditary cancer in the literature. This variant has been identified in 1/250072 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV002271510	SCV002556184	uncertain significance	not specified	2024-03-07	criteria provided, single submitter	clinical testing	Variant summary: BRCA2 c.6923A>C (p.Lys2308Thr) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 4e-06 in 250072 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.6923A>C has been reported in the literature in at-least one individual affected with hereditary breast cancer (Zayas-Villanueva_2019). This report does not provide unequivocal conclusions about association of the variant with Hereditary Breast And Ovarian Cancer Syndrome. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publication have been ascertained in the context of this evaluation (PMID: 31331294). ClinVar contains an entry for this variant (Variation ID: 421193). Based on the evidence outlined above, the variant was classified as uncertain significance.
Labcorp Genetics (formerly Invitae), Labcorp	RCV002526593	SCV002990434	uncertain significance	Hereditary breast ovarian cancer syndrome	2024-05-06	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 2308 of the BRCA2 protein (p.Lys2308Thr). This variant is present in population databases (rs186810431, gnomAD 0.003%). This missense change has been observed in individual(s) with breast cancer (PMID: 31331294). ClinVar contains an entry for this variant (Variation ID: 421193). 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 with a negative predictive value of 95%. 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.