13-32319101-G-T

Variant names:

• chr13-32319101-G-T
• rs397508045
• ENST00000530893:c.-278G>T

Variant summary

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

The NM_001406722.1(BRCA2):​c.-278G>T variant causes a 5 prime UTR premature start codon gain change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: BRCA2 NM_001406722.1 5_prime_UTR_premature_start_codon_gain
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:4
• Conservation: PhyloP100: 7.06

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 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
BRCA2	NM_000059.4	c.92G>T	p.Trp31Leu	missense_variant	Exon 3 of 27	ENST00000380152.8	NP_000050.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
BRCA2	ENST00000530893	c.-278G>T		5_prime_UTR_premature_start_codon_gain_variant	Exon 3 of 27	1		ENSP00000499438.2
BRCA2	ENST00000380152.8	c.92G>T	p.Trp31Leu	missense_variant	Exon 3 of 27	5	NM_000059.4	ENSP00000369497.3
BRCA2	ENST00000530893	c.-278G>T		5_prime_UTR_variant	Exon 3 of 27	1		ENSP00000499438.2
BRCA2	ENST00000614259.2	n.92G>T		non_coding_transcript_exon_variant	Exon 2 of 26	2		ENSP00000506251.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.00000399 AC: 1 AN: 250830 Hom.: 0 AF XY: 0.00000737 AC XY: 1 AN XY: 135776

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000544

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 33

ExAC AF: 0.00000824 AC: 1

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Breast and/or ovarian cancer Uncertain:1

Feb 15, 2022

CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Malignant tumor of pancreas Uncertain:1

Mar 07, 2017

3DMed Clinical Laboratory Inc

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Breast neoplasm Uncertain:1

Nov 01, 2015

Laboratory of Molecular Diagnosis of Cancer, West China Hospital, Sichuan University

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: research

- -

Hereditary cancer-predisposing syndrome Uncertain:1

Oct 30, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.W31L variant (also known as c.92G>T), located in coding exon 2 of the BRCA2 gene, results from a G to T substitution at nucleotide position 92. The tryptophan at codon 31 is replaced by leucine, an amino acid with similar properties. This variant was identified in 1/507 unselected Chinese breast cancer patients (Zhong X et al. PLoS One, 2016 Jun;11:e0156789). This amino acid position is highly 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.74
BayesDel_addAF	Benign	-0.057	T
BayesDel_noAF	Benign	-0.15
CADD	Uncertain	25
DANN	Uncertain	0.99
Eigen	Pathogenic	0.84
Eigen_PC	Pathogenic	0.83
FATHMM_MKL	Pathogenic	0.97	D
M_CAP	Benign	0.069	D
MetaRNN	Uncertain	0.68	D;D
MetaSVM	Benign	-1.2	T
PrimateAI	Uncertain	0.66	T
PROVEAN	Uncertain	-3.3	D;D
REVEL	Uncertain	0.35
Sift	Pathogenic	0.0	D;D
Sift4G	Pathogenic	0.0	D;D
Vest4		0.61
MutPred		0.62		Loss of catalytic residue at L29 (P = 0.0215);Loss of catalytic residue at L29 (P = 0.0215);
MVP		0.88
MPC		0.071
ClinPred		0.98	D
GERP RS		5.7
gMVP		0.69

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs397508045; hg19: chr13-32893238;