Submissions for variant NM_000059.4(BRCA2):c.1803A>C (p.Lys601Asn)

gnomAD frequency: 0.00003  dbSNP: rs768106492

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Color Diagnostics, LLC DBA Color Health	RCV000583149	SCV000688725	uncertain significance	Hereditary cancer-predisposing syndrome	2022-05-10	criteria provided, single submitter	clinical testing	This missense variant replaces lysine with asparagine at codon 601 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 detected in a breast cancer case-control meta-analysis in 0/60466 cases and 6/53461 unaffected individuals (PMID: 33471991; Leiden Open Variation Database DB-ID BRCA2_003057). This variant has been identified in 7/241228 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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000637541	SCV000759005	uncertain significance	Hereditary breast ovarian cancer syndrome	2024-12-12	criteria provided, single submitter	clinical testing	This sequence change replaces lysine, which is basic and polar, with asparagine, which is neutral and polar, at codon 601 of the BRCA2 protein (p.Lys601Asn). This variant is present in population databases (rs768106492, gnomAD 0.006%). This missense change has been observed in individual(s) with BRCA2-related conditions (PMID: 27449771). ClinVar contains an entry for this variant (Variation ID: 491210). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) 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.
Ambry Genetics	RCV000583149	SCV001173795	uncertain significance	Hereditary cancer-predisposing syndrome	2022-03-23	criteria provided, single submitter	clinical testing	The p.K601N variant (also known as c.1803A>C), located in coding exon 9 of the BRCA2 gene, results from an A to C substitution at nucleotide position 1803. The lysine at codon 601 is replaced by asparagine, an amino acid with similar properties. This alteration was identified in a cohort of pancreatic cancer patients undergoing whole exome sequencing (Yang XR et al. Hum Genet, 2016 Nov;135:1241-1249). This amino acid position is poorly conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
GeneDx	RCV001556198	SCV001777733	uncertain significance	not provided	2019-10-11	criteria provided, single submitter	clinical testing	Not observed at a significant frequency in large population cohorts (Lek 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge; Also known as BRCA2 2031A>C
University of Washington Department of Laboratory Medicine, University of Washington	RCV000583149	SCV003851654	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).
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV004525979	SCV005040605	uncertain significance	not specified	2024-03-28	criteria provided, single submitter	clinical testing	Variant summary: BRCA2 c.1803A>C (p.Lys601Asn) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 2.9e-05 in 241228 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.1803A>C has been reported in the literature in at-least one individual within a cohort with pancreatic cancer without germline CDKN2A variants (example, Yang_2016). These report(s) do 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. ClinVar contains an entry for this variant (Variation ID: 491210). Based on the evidence outlined above, the variant was classified as uncertain significance.
Clinical Genetics Laboratory, Skane University Hospital Lund	RCV001556198	SCV005199772	uncertain significance	not provided	2023-08-21	criteria provided, single submitter	clinical testing
BRCAlab, Lund University	RCV003493672	SCV004244232	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2020-03-02	no assertion criteria provided	clinical testing