Submissions for variant NM_000059.4(BRCA2):c.9161C>T (p.Pro3054Leu)

dbSNP: rs80359172

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000766655	SCV000210497	uncertain significance	not provided	2018-05-17	criteria provided, single submitter	clinical testing	This variant is denoted BRCA2 c.9161C>T at the cDNA level, p.Pro3054Leu (P3054L) at the protein level, and results in the change of a Proline to a Leucine (CCC>CTC). BRCA2 c.9161C>T, previously reported as c.9389C>T, has not, to our knowledge, been published in the literature as pathogenic or benign. BRCA2 Pro3054Leu was not observed in large population cohorts (Lek 2016). Since Proline and Leucine differ in some properties, this is considered a semi-conservative amino acid substitution. BRCA2 Pro3054Leu is located in the DNA binding domain (Yang 2002). In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function. Based on currently available information, it is unclear whether BRCA2 Pro3054Leu is pathogenic or benign. We consider it to be a variant of uncertain significance.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000160165	SCV000600847	uncertain significance	not specified	2017-04-12	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000573424	SCV000665981	uncertain significance	Hereditary cancer-predisposing syndrome	2024-07-29	criteria provided, single submitter	clinical testing	The p.P3054L variant (also known as c.9161C>T), located in coding exon 23 of the BRCA2 gene, results from a C to T substitution at nucleotide position 9161. The proline at codon 3054 is replaced by leucine, an amino acid with similar properties. This variant was reported in a high-risk breast and ovarian cancer cohort from the Netherlands and was classified as unlikely to be pathogenic based on in silico data and the national working group for Breast Cancer DNA Diagnostics classification algorithm (Moghadasi S et al. J Med Genet, 2013 Feb;50:74-9). In another study, this variant was reported in 1/60,466 breast cancer cases and in 0/53,461 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. Based on the available evidence, the clinical significance of this variant remains unclear.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000690429	SCV000818113	uncertain significance	Hereditary breast ovarian cancer syndrome	2024-05-15	criteria provided, single submitter	clinical testing	This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 3054 of the BRCA2 protein (p.Pro3054Leu). This variant is not present in population databases (gnomAD no frequency). 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: 182259). 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.
Color Diagnostics, LLC DBA Color Health	RCV000573424	SCV000906699	uncertain significance	Hereditary cancer-predisposing syndrome	2023-09-13	criteria provided, single submitter	clinical testing	This missense variant replaces proline with leucine at codon 3054 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 an individual affected with breast cancer (PMID: 33471991; Leiden Open Variation Database DB-ID BRCA2_001715). This variant has not been identified 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	RCV000160165	SCV002500149	uncertain significance	not specified	2022-03-07	criteria provided, single submitter	clinical testing	Variant summary: BRCA2 c.9161C>T (p.Pro3054Leu) results in a non-conservative amino acid change located in the oligonucleotide/oligosaccharide-binding, domain 3 (PF09104) of the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant was absent in 251260 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.9161C>T has been reported in the literature in individuals affected with Breast Cancer (e.g. Moghadasi_2013, Dorling_2021). These reports 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. Five ClinVar submitters have assessed the variant since 2014: all have classified the variant as of uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
All of Us Research Program, National Institutes of Health	RCV004804696	SCV004846131	uncertain significance	BRCA2-related cancer predisposition	2024-09-23	criteria provided, single submitter	clinical testing	This missense variant replaces proline with leucine at codon 3054 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 an individual affected with breast cancer (PMID: 33471991; Leiden Open Variation Database DB-ID BRCA2_001715). This variant has not been identified 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.