rs876658351

Positions:

• chr13-32396967-T-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.9571T>C​(p.Trp3191Arg) 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. 12/19 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:4
• Conservation: PhyloP100: 0.184

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=0.17387542).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
BRCA2	NM_000059.4	c.9571T>C	p.Trp3191Arg	missense_variant	26/27	ENST00000380152.8	NP_000050.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
BRCA2	ENST00000380152.8	c.9571T>C	p.Trp3191Arg	missense_variant	26/27	5	NM_000059.4	ENSP00000369497	A2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Hereditary cancer-predisposing syndrome Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Ambry Genetics	Jan 16, 2015	The p.W3191R variant (also known as c.9571T>C or 9799T>C), located in coding exon 25 of the BRCA2 gene, results from a T to C substitution at nucleotide position 9571. The tryptophan at codon 3191 is replaced by arginine, an amino acid with dissimilar properties. This alteration was previously identified in a familial breast cancer kindred in which the proband had been diagnosed with early-onset triple negative breast cancer (Lara K et al, Biol. Res. 2012 ; 45(2):117-30). This variant was not reported in population based cohorts in the following databases: Database of Single Nucleotide Polymorphisms (dbSNP), NHLBI Exome Sequencing Project (ESP), and 1000 Genomes Project. In the ESP, this variant was not observed in 6503 samples (13006 alleles) with coverage at this position. To date, this alteration has been detected with an allele frequency of approximately 0.001% (greater than 105,000 alleles tested) in our clinical cohort. Based on protein sequence alignment, this amino acid position is poorly 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 p.W3191R remains unclear -
Uncertain significance, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Jan 29, 2019	- -

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Quest Diagnostics Nichols Institute San Juan Capistrano

Dec 10, 2019

- -

Hereditary breast ovarian cancer syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Feb 21, 2022

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. 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. ClinVar contains an entry for this variant (Variation ID: 230046). This variant is also known as c.9799T>C. This missense change has been observed in individual(s) with breast cancer (PMID: 23096355). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces tryptophan, which is neutral and slightly polar, with arginine, which is basic and polar, at codon 3191 of the BRCA2 protein (p.Trp3191Arg). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.19
BayesDel_addAF	Benign	-0.14	T
BayesDel_noAF	Benign	-0.45
CADD	Benign	15
DANN	Benign	0.97
Eigen	Benign	-0.51
Eigen_PC	Benign	-0.45
FATHMM_MKL	Benign	0.054	N
M_CAP	Uncertain	0.17	D
MetaRNN	Benign	0.17	T;T
MetaSVM	Benign	-0.89	T
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.28	T
PROVEAN	Uncertain	-2.8	D;D
REVEL	Benign	0.098
Sift	Benign	0.11	T;T
Sift4G	Benign	0.078	T;T
Vest4		0.23
MutPred		0.48		Gain of disorder (P = 0.0115);Gain of disorder (P = 0.0115);
MVP		0.82
MPC		0.025
ClinPred		0.082	T
GERP RS		1.7
gMVP		0.25

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		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: rs876658351; hg19: chr13-32971104;