Submissions for variant NM_000059.4(BRCA2):c.437T>C (p.Leu146Pro)

dbSNP: rs539929888

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000129309	SCV000184071	uncertain significance	Hereditary cancer-predisposing syndrome	2022-08-17	criteria provided, single submitter	clinical testing	The p.L146P variant (also known as c.437T>C), located in coding exon 4 of the BRCA2 gene, results from a T to C substitution at nucleotide position 437. The leucine at codon 146 is replaced by proline, an amino acid with similar properties. This amino acid position is well 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000781114	SCV000918955	uncertain significance	not specified	2023-12-13	criteria provided, single submitter	clinical testing	Variant summary: BRCA2 c.437T>C (p.Leu146Pro) 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 4e-06 in 250866 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.437T>C in individuals affected with Hereditary Breast And Ovarian Cancer Syndrome and no experimental evidence demonstrating its impact on protein function have been reported. A report from the CAGI5 ENIGMA challenge has classified this variant as likely benign (Cline_2019). The following publication has been ascertained in the context of this evaluation (PMID: 31294896). Three submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000801053	SCV000940809	uncertain significance	Hereditary breast ovarian cancer syndrome	2022-08-08	criteria provided, single submitter	clinical testing	This sequence change replaces leucine, which is neutral and non-polar, with proline, which is neutral and non-polar, at codon 146 of the BRCA2 protein (p.Leu146Pro). This variant is present in population databases (rs539929888, gnomAD 0.003%). This variant has not been reported in the literature in individuals affected with BRCA2-related conditions. ClinVar contains an entry for this variant (Variation ID: 140997). 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.
Color Diagnostics, LLC DBA Color Health	RCV000129309	SCV001347749	uncertain significance	Hereditary cancer-predisposing syndrome	2023-07-17	criteria provided, single submitter	clinical testing	This missense variant replaces leucine with proline at codon 146 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 a multifactorial analysis with co-occurrence and family history likelihood ratios for pathogenicity of 1.0331 and 0.4348, respectively (PMID: 31131967). This variant has been identified in 1/250866 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.
Baylor Genetics	RCV003474745	SCV004211824	uncertain significance	Familial cancer of breast	2023-10-22	criteria provided, single submitter	clinical testing