chr13-32326139-G-A

Position:

• chr13-32326139-G-A

Variant summary

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

The NM_000059.4(BRCA2):​c.464G>A​(p.Arg155Lys) 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. 14/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency: Genomes: not found (cov: 33)
• Consequence: BRCA2 NM_000059.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:4 B:1
• Conservation: PhyloP100: 2.33

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]

BRCA2 (HGNC:):

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=0.23277059).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
BRCA2	NM_000059.4	c.464G>A	p.Arg155Lys	missense_variant	5/27	ENST00000380152.8	NP_000050.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
BRCA2	ENST00000380152.8	c.464G>A	p.Arg155Lys	missense_variant	5/27	5	NM_000059.4	ENSP00000369497.3
BRCA2	ENST00000530893.7	c.95G>A	p.Arg32Lys	missense_variant	5/27	1		ENSP00000499438.2
BRCA2	ENST00000614259.2	n.464G>A		non_coding_transcript_exon_variant	4/26	2		ENSP00000506251.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:4 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Familial cancer of breast Uncertain:1 Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Baylor Genetics	Mar 18, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	MGZ Medical Genetics Center	Feb 09, 2024	ACMG codes applied following ENIGMA VCEP rules: BP1_STR, PM2_SUP -

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

Uncertain significance, criteria provided, single submitter

clinical testing

Centro de Genética y Biología Molecular, Universidad de San Martín de Porres

Jun 06, 2016

No present in population-based study (100 controls) -

Hereditary cancer-predisposing syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Feb 08, 2021

The p.R155K variant (also known as c.464G>A), located in coding exon 4 of the BRCA2 gene, results from a G to A substitution at nucleotide position 464. The arginine at codon 155 is replaced by lysine, an amino acid with highly similar properties. This alteration has been detected in a Peruvian breast cancer patient and not in 100 Peruvian controls (Buleje J et al. Mol Genet Genomic Med. 2017 Jun 28;5(5):481-494). This amino acid position is 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

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 10, 2024

This sequence change replaces arginine, which is basic and polar, with lysine, which is basic and polar, at codon 155 of the BRCA2 protein (p.Arg155Lys). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with breast, ovarian, or unspecified cancer (PMID: 28944232, 32522261). ClinVar contains an entry for this variant (Variation ID: 253032). 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 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	0.11
BayesDel_addAF	Benign	-0.081	T
BayesDel_noAF	Benign	-0.35
CADD	Benign	20
DANN	Benign	0.97
Eigen	Benign	-0.32
Eigen_PC	Benign	-0.32
FATHMM_MKL	Benign	0.75	D
M_CAP	Benign	0.045	D
MetaRNN	Benign	0.23	T;T
MetaSVM	Benign	-0.91	T
PrimateAI	Benign	0.45	T
PROVEAN	Benign	-0.66	N;N
REVEL	Benign	0.20
Sift	Benign	0.13	T;T
Sift4G	Benign	0.63	T;T
Vest4		0.47
MutPred		0.37		Gain of methylation at R155 (P = 0.0113);Gain of methylation at R155 (P = 0.0113);
MVP		0.86
MPC		0.15
ClinPred		0.35	T
GERP RS		2.2
gMVP		0.36

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: rs377639990; hg19: chr13-32900276; COSMIC: COSV66464026;