Submissions for variant NM_000059.4(BRCA2):c.663T>G (p.Phe221Leu)

gnomAD frequency: 0.00003  dbSNP: rs80358891

Total submissions: 11

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen ENIGMA BRCA1 and BRCA2 Variant Curation Expert Panel, ClinGen	RCV004566773	SCV004101434	likely benign	BRCA2-related cancer predisposition	2024-06-11	reviewed by expert panel	curation	The c.663T>G variant in BRCA2 is a missense variant predicted to cause substitution of Phenylalanine by Leucine at amino acid 221 (p.Phe221Leu). This variant is present in gnomAD v2.1 (exomes only, non-cancer subset) or gnomAD v3.1 (non-cancer subset) but is below the ENIGMA BRCA1/2 VCEP threshold >0.00002 for BS1_Supporting (PM2_Supporting, BS1, and BA1 are not met). This missense variant is located outside of a key functional domain and was not predicted to alter mRNA splicing using the SpliceAI predictor (score 0, score threshold <0.1) (BP1_Strong met). Multifactorial likelihood ratio analysis using clinically calibrated data produced a combined LR for this variant of 1.396 (based on Co-occurrence LR=1.08; Family History LR=1.3), which is above the ENIGMA BRCA1/2 VCEP threshold for BP5 (>0.48) and below PP4 (<2.08) (BP5 and PP4 not met; PMID: 31131967, 31853058). In summary, this variant meets the criteria to be classified as a Likely benign variant for BRCA2-related cancer predisposition based on the ACMG/AMP criteria applied as specified by the ENIGMA BRCA1/2 VCEP (BP1_Strong).
Ambry Genetics	RCV000132202	SCV000187284	uncertain significance	Hereditary cancer-predisposing syndrome	2022-10-04	criteria provided, single submitter	clinical testing	The p.F221L variant (also known as c.663T>G), located in coding exon 7 of the BRCA2 gene, results from a T to G substitution at nucleotide position 663. The phenylalanine at codon 221 is replaced by leucine, an amino acid with highly similar properties. This alteration was identified in an individual considered high risk for breast and/or ovarian cancer (Lu W et al. Fam Cancer, 2012 Sep;11:381-5). This amino acid position is not well 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	RCV000759646	SCV000329131	uncertain significance	not provided	2021-08-11	criteria provided, single submitter	clinical testing	Observed in an individual with a personal and/or family history of breast and/or ovarian cancer (Lu 2012); In silico analysis supports that this missense variant does not alter protein structure/function; Not observed at significant frequency in large population cohorts (Lek 2016); Also known as 891T>G; This variant is associated with the following publications: (PMID: 22476429, 31131967)
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000759646	SCV000889108	uncertain significance	not provided	2020-02-27	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000781125	SCV000918973	uncertain significance	not specified	2023-09-11	criteria provided, single submitter	clinical testing	Variant summary: BRCA2 c.663T>G (p.Phe221Leu) results in a non-conservative amino acid change in the encoded protein sequence. Two of four in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 4.1e-06 in 245048 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.663T>G has been reported in the literature in an individual affected with breast cancer from a high-risk breast/ovarian cancer family (Lu_2012). This report does 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. The following publication have been ascertained in the context of this evaluation (PMID: 22476429). Five 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.
Color Diagnostics, LLC DBA Color Health	RCV000132202	SCV001339315	uncertain significance	Hereditary cancer-predisposing syndrome	2023-10-05	criteria provided, single submitter	clinical testing	This missense variant replaces phenylalanine with leucine at codon 221 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 or ovarian cancer (PMID: 22476429) and in a multifactorial analysis with co-occurrence and family history likelihood ratios for pathogenicity of 1.0756 and 3.2237, respectively (PMID: 31131967). 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.
Invitae	RCV001368968	SCV001565393	uncertain significance	Hereditary breast ovarian cancer syndrome	2024-01-16	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 221 of the BRCA2 protein (p.Phe221Leu). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This missense change has been observed in individual(s) with breast cancer (PMID: 22476429). ClinVar contains an entry for this variant (Variation ID: 38058). 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.
Baylor Genetics	RCV003460523	SCV004213648	uncertain significance	Familial cancer of breast	2023-08-23	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV000031640	SCV004846803	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2023-11-02	criteria provided, single submitter	clinical testing	This missense variant replaces phenylalanine with leucine at codon 221 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 or ovarian cancer (PMID: 22476429) and in a multifactorial analysis with co-occurrence and family history likelihood ratios for pathogenicity of 1.0756 and 3.2237, respectively (PMID: 31131967). 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.
Sharing Clinical Reports Project (SCRP)	RCV000031640	SCV000054247	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2009-02-03	no assertion criteria provided	clinical testing
Breast Cancer Information Core (BIC) (BRCA2)	RCV000031640	SCV000147440	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2000-07-07	no assertion criteria provided	clinical testing