Submissions for variant NM_000059.4(BRCA2):c.1816C>T (p.Pro606Ser)

dbSNP: rs765924757

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000585914	SCV000694564	uncertain significance	not provided	2017-01-02	criteria provided, single submitter	clinical testing	Variant summary: The BRCA2 c.1816C>T (p.Pro606Ser) variant involves the alteration of a non-conserved nucleotide and is predicted to be damaging by 3/5 in silico tools. This variant is absent in 117916 control chromosomes from ExAC. This variant was found in one HBOC patient in literature without strong evidence for pathogenicity and they authors also classify it as a UV (unclassified variant). One internal sample carrying this variant also carries another possibly pathogenic variant BRCA1 c.2068_2082del15. Taken together, this variant is classified as Variant of Uncertain Significance
Labcorp Genetics (formerly Invitae), Labcorp	RCV000814790	SCV000955216	uncertain significance	Hereditary breast ovarian cancer syndrome	2024-04-04	criteria provided, single submitter	clinical testing	This sequence change replaces proline, which is neutral and non-polar, with serine, which is neutral and polar, at codon 606 of the BRCA2 protein (p.Pro606Ser). This variant is present in population databases (no rsID available, gnomAD 0.0009%). This missense change has been observed in individual(s) with breast and/or ovarian cancer (PMID: 18060494, 21520333). This variant is also known as 2044C>T. ClinVar contains an entry for this variant (Variation ID: 495434). 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.
Ambry Genetics	RCV002413663	SCV002711988	uncertain significance	Hereditary cancer-predisposing syndrome	2021-11-24	criteria provided, single submitter	clinical testing	The p.P606S variant (also known as c.1816C>T), located in coding exon 9 of the BRCA2 gene, results from a C to T substitution at nucleotide position 1816. The proline at codon 606 is replaced by serine, an amino acid with similar properties. This variant is also known as c.2044C>T and has been reported in the literature in an individual with a family history of hereditary breast and ovarian cancer (Esteban Cardeñosa E et al. Breast Cancer Res Treat, 2008 Nov;112:69-73) and in 2/60,466 breast cancer cases and 1/53,461 controls (Dorling et al. N Engl J Med. 2021 02;384:428-439). 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.
University of Washington Department of Laboratory Medicine, University of Washington	RCV002413663	SCV003851663	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).
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	RCV000585914	SCV001963006	likely benign	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000585914	SCV001975955	likely benign	not provided		no assertion criteria provided	clinical testing