Submissions for variant NM_000059.4(BRCA2):c.7914T>G (p.Phe2638Leu)

gnomAD frequency: 0.00002  dbSNP: rs764248927

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000167304	SCV000218147	uncertain significance	Hereditary cancer-predisposing syndrome	2024-06-09	criteria provided, single submitter	clinical testing	The p.F2638L variant (also known as c.7914T>G), located in coding exon 16 of the BRCA2 gene, results from a T to G substitution at nucleotide position 7914. The phenylalanine at codon 2638 is replaced by leucine, an amino acid with highly similar properties. In one case-control study, this variant, referred to as F2638L (8142T>G), was observed in 1/1398 controls (defined as having unilateral breast cancer) and in 0/705 cases (defined as having contralateral breast cancer) (Borg A et al. Hum Mutat. 2010 Mar; 31(3):E1200-40). In a different case-control study, this variant was reported in 1/60,466 breast cancer cases and in 1/53,461 controls (Dorling et al. N Engl J Med. 2021 02;384:428-439). In addition, in a study of whole-exome sequencing in patients with features of Cowden syndrome (CS) or Bannayan-Riley-Ruvalcaba syndrome (BRRS) and negative PTEN testing, this alteration was identified in 0/87 patients with CS or BRRS and 1/3476 patients from The Cancer Genome Atlas (TCGA) (Yehia L et al. PLoS Genet, 2018 04;14:e1007352). This amino acid position is highly 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.
GeneDx	RCV000480378	SCV000566458	uncertain significance	not provided	2023-08-01	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant does not alter protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); Also known as 8142T>G; This variant is associated with the following publications: (PMID: 12228710, 20104584, 32377563, 29684080, 33471991)
Labcorp Genetics (formerly Invitae), Labcorp	RCV000533964	SCV000635615	uncertain significance	Hereditary breast ovarian cancer syndrome	2023-10-05	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 2638 of the BRCA2 protein (p.Phe2638Leu). This variant is present in population databases (rs764248927, gnomAD 0.004%). This missense change has been observed in individual(s) with breast cancer (PMID: 20104584). ClinVar contains an entry for this variant (Variation ID: 187565). 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	RCV000167304	SCV001344659	uncertain significance	Hereditary cancer-predisposing syndrome	2023-03-08	criteria provided, single submitter	clinical testing	This missense variant replaces phenylalanine with leucine at codon 2638 of the BRCA2 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, 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: 20104584). This variant has been identified in 4/251282 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	RCV003474888	SCV004211867	uncertain significance	Familial cancer of breast	2023-10-16	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV003493478	SCV004845571	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2023-08-08	criteria provided, single submitter	clinical testing	This missense variant replaces phenylalanine with leucine at codon 2638 of the BRCA2 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). Splice site prediction tools suggest that this variant may not impact RNA splicing. To our knowledge, functional studies have not been performed for this variant. This variant has been reported in 1 individual affected with breast cancer (PMID: 20104584). This variant has been identified in 4/251282 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.
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001355608	SCV001550540	uncertain significance	Malignant tumor of breast		no assertion criteria provided	clinical testing	The BRCA2 p.Phe2638Leu variant was identified in 1 of 4206 proband chromosomes (frequency: 0.0002) from individuals with breast cancer (Borg 2010). The variant was identified in dbSNP (rs764248927) as “with uncertain significance allele” and ClinVar (classified as uncertain significance by Invitae, Ambry Genetics and GeneDx). The variant was not identified in LOVD 3.0 and UMD-LSDB. The variant was identified in control databases in 4 of 246,046 chromosomes at a frequency of 0.00002 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following population: European in 4 of 111,518 chromosomes (freq: 0.00004), but not in the African, Other, Latino, Ashkenazi Jewish, East Asian, Finnish or South Asian populations. The p.Phe2638 residue is conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) provide inconsistent predictions regarding the impact to the protein; this information is not very predictive of pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. In summary, based on the above information, the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance.
BRCAlab, Lund University	RCV003493478	SCV004243788	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2020-03-02	no assertion criteria provided	clinical testing