Submissions for variant NM_000059.4(BRCA2):c.8452G>T (p.Val2818Phe)

dbSNP: rs80359094

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000566230	SCV000666160	uncertain significance	Hereditary cancer-predisposing syndrome	2024-04-08	criteria provided, single submitter	clinical testing	The p.V2818F variant (also known as c.8452G>T), located in coding exon 18 of the BRCA2 gene, results from a G to T substitution at nucleotide position 8452. The valine at codon 2818 is replaced by phenylalanine, an amino acid with highly similar properties. This alteration has been reported in a breast cancer patient (Abulkhair O et al. J Glob Oncol, 2018 Aug;4:1-9). This alteration has also been reported in the homozygous state in an individual with anemia, leukopenia, thrombocytopenia, and was called a variant of uncertain significance by study authors (AlAbdi L et al. Nat Commun, 2023 Aug;14:5269). This amino acid position is not well 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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001320393	SCV001511175	uncertain significance	Hereditary breast ovarian cancer syndrome	2021-09-02	criteria provided, single submitter	clinical testing	This sequence change replaces valine with phenylalanine at codon 2818 of the BRCA2 protein (p.Val2818Phe). The valine residue is highly conserved and there is a small physicochemical difference between valine and phenylalanine. This variant is not present in population databases (ExAC no frequency). This missense change has been observed in individual(s) with breast cancer (PMID: 30199306). ClinVar contains an entry for this variant (Variation ID: 481607). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). 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.
Genetic Services Laboratory, University of Chicago	RCV001821668	SCV002070244	uncertain significance	not specified	2020-06-11	criteria provided, single submitter	clinical testing	DNA sequence analysis of the BRCA2 gene demonstrated a sequence change, c.8452G>T, in exon 19 that results in an amino acid change, p.Val2818Phe. This sequence change has not been described in population databases (gnomAD, ExAC). The p.Val2818Phe change has been reported in one Saudi Arabian individual with breast cancer (PMID: 30199306). The p.Val2818Phe change affects a highly conserved amino acid residue located in a domain of the BRCA2 protein that is known to be functional. In-silico pathogenicity prediction tools (SIFT, PolyPhen2, Align GVGD, REVEL) provide contradictory results for the p.Val2818Phe substitution. Due to these contrasting evidences and the lack of functional studies, the clinical significance of the p.Val2818Phe change remains unknown at this time.
Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center	RCV003227793	SCV003924290	likely pathogenic	Fanconi anemia complementation group D1	2023-05-08	criteria provided, single submitter	research
KCCC/NGS Laboratory, Kuwait Cancer Control Center	RCV003234782	SCV003932765	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2023-06-06	criteria provided, single submitter	clinical testing	A variant of uncertain significance was detected in this sample. This sequence change replaces valine at codon 2818 is by phenylalanine, an amino acid with highly similar properties., which located in coding exon 19 of the BRCA2 gene (NM_000059.3), results from a G to T substitution at nucleotide position 8452. This amino acid position is not highly conserved. This variant is not present in population databases (gnomAD ) nor in our local databases . This variant reported in ClinVar database (ID: 481607) .Also it was previously reported in one Saudi Arabian individual with breast cancer (PMID: 30199306). This alteration is predicted to be possibly damaging and deleterious by (PolyPhen , EIGEN PC, FATHMM , LRT,Mutation taster , DANN, M-CAP, MVP , Align GVGD, REVEL and SIFT). In summary, Due to these contrasting evidences and the lack of functional studies, the clinical significance of the p.Val2818Phe change remains unknown at this time. Therefore, it has been classified as a Variant of Uncertain Significance.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001821668	SCV004804499	uncertain significance	not specified	2024-01-12	criteria provided, single submitter	clinical testing	Variant summary: BRCA2 c.8452G>T (p.Val2818Phe) results in a non-conservative amino acid change located in the OB2 domain (IPR048262) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 251400 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.8452G>T has been reported in the literature in individuals from Saudi Arabia, including at least one individual affected with breast cancer (e.g., Abulkhair_2018), as well as a homozygous individual for whom clinical details were not provided, although the individual was reported to have a sibling with leukemia and suspected Fanconi anemia (e.g., AlAbdi_2021, Monies_2023). 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. The following publications have been ascertained in the context of this evaluation (PMID: 30199306, 34316023, 37344829). ClinVar contains an entry for this variant (Variation ID: 481607). Based on the evidence outlined above, the variant was classified as uncertain significance.
All of Us Research Program, National Institutes of Health	RCV003234782	SCV004826380	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2023-08-15	criteria provided, single submitter	clinical testing	This missense variant replaces valine with phenylalanine at codon 2818 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: 30199306). 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.
BRCAlab, Lund University	RCV003234782	SCV004243820	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2020-03-02	no assertion criteria provided	clinical testing