13-32370522-G-T

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP3

The NM_000059.4(BRCA2):c.8452G>T(p.Val2818Phe) variant causes a missense change. The variant allele was found at a frequency of 0.000000684 in 1,461,572 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V2818I) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: BRCA2 NM_000059.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:7
• Conservation: PhyloP100: 5.57

Genes affected

BRCA2 (HGNC:1101): (BRCA2 DNA repair associated) Inherited mutations in BRCA1 and this gene, BRCA2, confer increased lifetime risk of developing breast or ovarian cancer. Both BRCA1 and BRCA2 are involved in maintenance of genome stability, specifically the homologous recombination pathway for double-strand DNA repair. The largest exon in both genes is exon 11, which harbors the most important and frequent mutations in breast cancer patients. The BRCA2 gene was found on chromosome 13q12.3 in human. The BRCA2 protein contains several copies of a 70 aa motif called the BRC motif, and these motifs mediate binding to the RAD51 recombinase which functions in DNA repair. BRCA2 is considered a tumor suppressor gene, as tumors with BRCA2 mutations generally exhibit loss of heterozygosity (LOH) of the wild-type allele. [provided by RefSeq, May 2020]

ACMG classification

Verdict is Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.76

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
BRCA2	NM_000059.4	c.8452G>T	p.Val2818Phe	missense_variant	19/27	ENST00000380152.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
BRCA2	ENST00000380152.8	c.8452G>T	p.Val2818Phe	missense_variant	19/27	5	NM_000059.4	A2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461572 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 727134

Gnomad4 AFR exome AF: 0.0000299

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1 Uncertain:7

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Breast-ovarian cancer, familial, susceptibility to, 2 Uncertain:3

Uncertain significance, criteria provided, single submitter	clinical testing	All of Us Research Program, National Institutes of Health	Aug 15, 2023	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. -
Uncertain significance, no assertion criteria provided	clinical testing	BRCAlab, Lund University	Mar 02, 2020	- -
Uncertain significance, criteria provided, single submitter	clinical testing	KCCC/NGS Laboratory, Kuwait Cancer Control Center	Jun 06, 2023	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. -

not specified Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jan 12, 2024	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. -
Uncertain significance, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Jun 11, 2020	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. -

Fanconi anemia complementation group D1 Pathogenic:1

Likely pathogenic, criteria provided, single submitter

research

Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center

May 08, 2023

- -

Hereditary cancer-predisposing syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 11, 2019

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 amino acid position is not well 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. -

Hereditary breast ovarian cancer syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Sep 02, 2021

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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.35
BayesDel_addAF	Pathogenic	0.16	D
BayesDel_noAF	Uncertain	0.0
Cadd	Uncertain	23
Dann	Uncertain	0.99
Eigen	Uncertain	0.62
Eigen_PC	Uncertain	0.57
FATHMM_MKL	Pathogenic	0.98	D
M_CAP	Uncertain	0.12	D
MetaRNN	Pathogenic	0.76	D;D
MetaSVM	Uncertain	-0.019	T
MutationTaster	Benign	1.0	D;D
PrimateAI	Benign	0.40	T
PROVEAN	Benign	-1.1	N;N
REVEL	Uncertain	0.39
Sift	Uncertain	0.0010	D;D
Sift4G	Uncertain	0.0030	D;D
Vest4		0.78
MutPred		0.34		Loss of sheet (P = 0.0817);Loss of sheet (P = 0.0817);
MVP		0.94
MPC		0.16
ClinPred		0.95	D
GERP RS		5.2
gMVP		0.81

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs80359094; hg19: chr13-32944659;