Submissions for variant NM_000059.4(BRCA2):c.3723T>G (p.Phe1241Leu)

dbSNP: rs587782723

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000132213	SCV000187295	uncertain significance	Hereditary cancer-predisposing syndrome	2024-04-03	criteria provided, single submitter	clinical testing	The p.F1241L variant (also known as c.3723T>G), located in coding exon 10 of the BRCA2 gene, results from a T to G substitution at nucleotide position 3723. The phenylalanine at codon 1241 is replaced by leucine, an amino acid with highly similar properties. This alteration has been reported in patients with a personal and/or family history of breast and/or ovarian cancer (Caux-Moncoutier V et al. Hum Mutat. 2011 Mar;32(3):325-34; Kanchi KL et al. Nat Commun. 2014;5:3156; Santonocito C et al. Cancers (Basel). 2020 May;12; Yao L et al. J Hum Genet, 2022 Nov;67:639-642). This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Based on the available evidence, the clinical significance of this variant remains unclear.
Centre for Mendelian Genomics, University Medical Centre Ljubljana	RCV000414919	SCV000492621	uncertain significance	Malignant tumor of prostate; Prostate neoplasm	2015-12-04	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000471263	SCV000549725	uncertain significance	Hereditary breast ovarian cancer syndrome	2025-01-02	criteria provided, single submitter	clinical testing	This sequence change replaces phenylalanine, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 1241 of the BRCA2 protein (p.Phe1241Leu). This variant is present in population databases (rs587782723, gnomAD 0.0009%). This missense change has been observed in individual(s) with a personal and/or family history of breast and/or ovarian cancer (PMID: 21120943, 24448499, 26689913, 32438681). ClinVar contains an entry for this variant (Variation ID: 142795). 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.
GeneDx	RCV000478604	SCV000566583	uncertain significance	not provided	2023-09-05	criteria provided, single submitter	clinical testing	Identified in individuals with a personal or family history of ovarian and/or breast cancer (Kanchi et al., 2014; Santonocito et al, 2020; Caux-Moncoutier et al., 2011); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Also known as 3951T>G; This variant is associated with the following publications: (PMID: 24448499, 21120943, 31911673, 32377563, 29884841, 31853058, 32438681, 9002670, 22193408, 26689913)
Centre for Mendelian Genomics, University Medical Centre Ljubljana	RCV001196211	SCV001366758	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2016-01-01	criteria provided, single submitter	clinical testing	This variant was classified as: Uncertain significance.
University of Washington Department of Laboratory Medicine, University of Washington	RCV000132213	SCV003846822	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).
All of Us Research Program, National Institutes of Health	RCV004804660	SCV004845210	uncertain significance	BRCA2-related cancer predisposition	2024-05-30	criteria provided, single submitter	clinical testing	This missense variant replaces phenylalanine with leucine at codon 1241 of the BRCA2 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in individuals affected with breast or ovarian cancer (PMID: 21120943, 24448499, 26689913, 32438681). This variant has been identified in 1/248448 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.
Molecular Diagnostics Laboratory, Catalan Institute of Oncology	RCV000132213	SCV005901863	likely benign	Hereditary cancer-predisposing syndrome	2025-02-19	criteria provided, single submitter	clinical testing	PM2_Supporting, BP1_Strong c.3723T>G, located in exon 11 of the BRCA2 gene, is predicted to result in the substitution of phenylalanine by leucine at codon 1241, p.(Phe1241Leu). This position is outside a (potentially) clinically important functional domain and, moreover, the SpliceAI algorithm predicts no significant impact on splicing (BP1_strong). It is not present in the population database gnomAD v2.1.1, non-cancer dataset (PM2_supporting). This variant has been found in breast and/or ovarian cancer-affected patients (PMID: 24448499, 32438681, and data from our internal cohort of patients) This variant has been reported in the ClinVar database (5x uncertain significance, 1x likely benign), in the LOVD database (1x uncertain significance) and in BRCA Exchange database (not yet classified). Based on currently available information, the variant c.3723T>G should be considered an uncertain significance variant according to ClinGen ENIGMA BRCA1 and BRCA2 Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for BRCA2 Version 1.0.0.