13-32319102-G-T

Variant names:

• chr13-32319102-G-T
• rs80359214
• NM_000059.4:c.93G>T

Variant summary

Our verdict is Likely pathogenic. The variant received 7 ACMG points: 7P and 0B. PM1 PM2 PM5 PP5

The NM_000059.4(BRCA2):​c.93G>T​(p.Trp31Cys) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Uncertain significance in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. W31G) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 33)
• Consequence: BRCA2 NM_000059.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:2
• Conservation: PhyloP100: 7.06
• Publications: 47 publications found

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 Gene-Disease associations (from GenCC):

• breast-ovarian cancer, familial, susceptibility to, 2

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Ambry Genetics, Genomics England PanelApp, Labcorp Genetics (formerly Invitae), ClinGen
• Fanconi anemia complementation group D1

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics, ClinGen, G2P
• pancreatic cancer, susceptibility to, 2

  Inheritance: AD Classification: STRONG Submitted by: Genomics England PanelApp
• sarcoma

  Inheritance: AD Classification: MODERATE Submitted by: Genomics England PanelApp
• hereditary breast ovarian cancer syndrome

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• Fanconi anemia

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• medulloblastoma

  Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics

ACMG classification

Our verdict: Likely_pathogenic. The variant received 7 ACMG points.

• PM1: In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 5 benign, 36 uncertain in NM_000059.4
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr13-32319100-T-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 481540.
• PP5: Variant 13-32319102-G-T is Pathogenic according to our data. Variant chr13-32319102-G-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 52830.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
BRCA2	NM_000059.4	c.93G>T	p.Trp31Cys	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	ENST00000380152.8	c.93G>T	p.Trp31Cys	missense_variant	Exon 3 of 27	5	NM_000059.4	ENSP00000369497.3
BRCA2	ENST00000614259.2	n.93G>T		non_coding_transcript_exon_variant	Exon 2 of 26	2		ENSP00000506251.1
BRCA2	ENST00000530893.7	c.-277G>T		5_prime_UTR_variant	Exon 3 of 27	1		ENSP00000499438.2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 33

Alfa AF: 0.000132 Hom.: 0

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1 Uncertain:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Hereditary breast ovarian cancer syndrome Pathogenic:1

Jan 15, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces tryptophan, which is neutral and slightly polar, with cysteine, which is neutral and slightly polar, at codon 31 of the BRCA2 protein (p.Trp31Cys). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with breast and/or ovarian cancer (PMID: 22678057; internal data). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 52830). 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%. Experimental studies have shown that this missense change affects BRCA2 function (PMID: 16793542, 20215541, 22194698, 22678057, 24285729). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. This variant disrupts the p.Trp31 amino acid residue in BRCA2. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 11149425, 30093976, 30410870, 31742824, 32778078; internal data). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. -

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

-

Breast Cancer Information Core (BIC) (BRCA2)

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Hereditary cancer-predisposing syndrome Uncertain:1

Aug 31, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.W31C variant (also known as c.93G>T), located in coding exon 2 of the BRCA2 gene, results from a G to T substitution at nucleotide position 93. The tryptophan at codon 31 is replaced by cysteine, an amino acid with highly dissimilar properties. Multiple in vitro functional studies have reported that p.W31C impairs BRCA2 homologous recombination (HR) function and PALB2 binding activity (Siaud N et al. PLoS Genet., 2011 Dec;7:e1002409; Al Abo M et al. Cancer Res., 2014 Feb;74:797-807; Oliver AW et al. EMBO Rep., 2009 Sep;10:990-6; Xia B et al. Mol. Cell, 2006 Jun;22:719-29; Biswas K et al. Hum. Mol. Genet., 2012 Sep;21:3993-4006; Shimelis H et al. Cancer Res., 2017 06;77:2789-2799; Mesman RLS et al. Genet. Med., 2018 Jul; Caleca L et al. Front Oncol. 2018 Oct;8:480; Ikegami M et al. Nat Commun. 2020 May;11(1):2573; Thomassen M et al. Hum Mutat. 2022 Dec;43(12):1921-1944). This amino acid position is highly 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.96
BayesDel_addAF	Uncertain	0.10	D
BayesDel_noAF	Benign	-0.090
CADD	Pathogenic	28
DANN	Uncertain	0.99
Eigen	Pathogenic	0.84
Eigen_PC	Pathogenic	0.83
FATHMM_MKL	Pathogenic	0.97	D
M_CAP	Benign	0.070	D
MetaRNN	Uncertain	0.70	D;D
MetaSVM	Benign	-1.2	T
PhyloP100		7.1
PrimateAI	Uncertain	0.66	T
PROVEAN	Uncertain	-3.3	D;D
REVEL	Uncertain	0.42
Sift	Pathogenic	0.0	D;D
Sift4G	Pathogenic	0.0	D;D
Vest4		0.59
MutPred		0.63		Gain of disorder (P = 0.0154);Gain of disorder (P = 0.0154);
MVP		0.87
MPC		0.029
ClinPred		0.99	D
GERP RS		5.7
gMVP		0.82
Mutation Taster		=28/72	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
Splicevardb		3.0
SpliceAI score (max)		0.030		Details are displayed if max score is > 0.2

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

Other links and lift over

dbSNP: rs80359214; hg19: chr13-32893239;