rs397507335

Variant names:

• chr13-32326126-G-A
• rs397507335
• NM_000059.4:c.451G>A

Your query was ambiguous. Multiple possible variants found:

• chr13-32326126-G-A
• chr13-32326126-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_000059.4(BRCA2):​c.451G>A​(p.Val151Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 13/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: BRCA2 NM_000059.4 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:5
• Conservation: PhyloP100: 0.732

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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.12956661).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
BRCA2	NM_000059.4	c.451G>A	p.Val151Ile	missense_variant	Exon 5 of 27	ENST00000380152.8	NP_000050.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
BRCA2	ENST00000380152.8	c.451G>A	p.Val151Ile	missense_variant	Exon 5 of 27	5	NM_000059.4	ENSP00000369497.3
BRCA2	ENST00000530893.7	c.82G>A	p.Val28Ile	missense_variant	Exon 5 of 27	1		ENSP00000499438.2
BRCA2	ENST00000614259.2	n.451G>A		non_coding_transcript_exon_variant	Exon 4 of 26	2		ENSP00000506251.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Breast-ovarian cancer, familial, susceptibility to, 2 Uncertain:1

Dec 23, 2009

Sharing Clinical Reports Project (SCRP)

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

BRCA2-related disorder Uncertain:1

Oct 24, 2022

PreventionGenetics, part of Exact Sciences

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The BRCA2 c.451G>A variant is predicted to result in the amino acid substitution p.Val151Ile. To our knowledge, this variant (referred to as 679G>A using legacy nomenclature) has not been reported in the literature in association with BRCA2-related disease. Results from a minigene assay suggest that this variant predominantly results in skipping of exon 5 and occasionally both exons 5 and 6 (Fraile-Bethencourt et al. 2019. PubMed ID: 30883759); however even the wild type minigene construct had both of these events and it is unclear if the results from these experiments accurately represent in vivo splicing. Computational splicing prediction programs predict that this variant would likely not have an impact on splicing (Alamut Visual Plus v1.6.1). This variant has not been reported in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. In ClinVar, this variant is interpreted as uncertain (https://www.ncbi.nlm.nih.gov/clinvar/variation/37908). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

not provided Uncertain:1

Mar 03, 2023

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; Published functional studies using a minigene assay demonstrate aberrant splicing and predict a truncated protein product (Fraile-Bethencourt et al., 2019); Also known as 679G>A; This variant is associated with the following publications: (PMID: 32623769, 30883759) -

Hereditary cancer-predisposing syndrome Uncertain:1

May 22, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.V151I variant (also known as c.451G>A), located in coding exon 4 of the BRCA2 gene, results from a G to A substitution at nucleotide position 451. The valine at codon 151 is replaced by isoleucine, an amino acid with highly similar properties. A minigene assay demonstrated that this alteration results in skipping of coding exon 4 in over 89% of transcripts (Fraile-Bethencourt E et al. J Pathol, 2019 08;248:409-420); however RNA studies have demonstrated that this alteration does not result in abnormal splicing in the set of samples tested (Ambry internal data). 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. -

Hereditary breast ovarian cancer syndrome Uncertain:1

Oct 22, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces valine, which is neutral and non-polar, with isoleucine, which is neutral and non-polar, at codon 151 of the BRCA2 protein (p.Val151Ile). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with BRCA2-related conditions. ClinVar contains an entry for this variant (Variation ID: 37908). 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.083
BayesDel_addAF	Benign	-0.099	T
BayesDel_noAF	Benign	-0.38
CADD	Benign	7.1
DANN	Benign	0.78
Eigen	Benign	-0.65
Eigen_PC	Benign	-0.70
FATHMM_MKL	Benign	0.013	N
M_CAP	Uncertain	0.13	D
MetaRNN	Benign	0.13	T;T
MetaSVM	Benign	-0.89	T
PrimateAI	Benign	0.30	T
PROVEAN	Benign	-0.22	N;N
REVEL	Benign	0.17
Sift	Benign	0.33	T;T
Sift4G	Benign	0.28	T;T
Vest4		0.24
MutPred		0.21		Gain of catalytic residue at P153 (P = 0.0305);Gain of catalytic residue at P153 (P = 0.0305);
MVP		0.73
MPC		0.021
ClinPred		0.15	T
GERP RS		2.9
gMVP		0.065

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: rs397507335; hg19: chr13-32900263;