13-32319102-G-T

Position:

• chr13-32319102-G-T

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. 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 variant affecting the same amino acid position, but resulting in a different missense (i.e. W31R) 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

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 5 ACMG points.

• 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-A is described in Lovd as [Likely_pathogenic].
• 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 id is 52830.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=1, Likely_pathogenic=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
BRCA2	NM_000059.4	c.93G>T	p.Trp31Cys	missense_variant	3/27	ENST00000380152.8	NP_000050.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
BRCA2	ENST00000380152.8	c.93G>T	p.Trp31Cys	missense_variant	3/27	5	NM_000059.4	ENSP00000369497.3
BRCA2	ENST00000530893	c.-277G>T		5_prime_UTR_variant	3/27	1		ENSP00000499438.2
BRCA2	ENST00000614259.2	n.93G>T		non_coding_transcript_exon_variant	2/26	2		ENSP00000506251.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 33

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

Likely pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Mar 06, 2020

In summary, this variant is a rare missense change that has been reported in affected individuals and shown to impair BRCA2 protein function. This evidence indicates that the variant is pathogenic, but additional data is needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. This missense change is located within the functionally conserved PALB2-binding domain of the BRCA2 protein (PMID: 19609323), and previously reported BRCA2 missense mutations and deletions have been found within this domain (PMID: 16793542, 22678057, 21939546). These observations suggest that a missense substitution within this domain may affect protein function. Experimental studies have shown that this missense change disrupts the binding of BRCA2 to PALB2, thereby abolishing the normal cellular functioning of BRCA2 (PMID: 16793542, 22678057, 24285729, 20215541, 22194698, 19609323, 30410870). Studies also suggest that this missense change may induce skipping of exon 3, and loss of exon 3 has been reported in several families affected with breast and/or ovarian cancer (PMID: 22678057, 20215541, 9537232, 21939546, 18363094). This variant has been reported in families affected with breast and/or ovarian cancer (PMID: 22678057, Invitae). ClinVar contains an entry for this variant (Variation ID: 52830). This variant is not present in population databases (rs80359214, ExAC no frequency). This sequence change replaces tryptophan with cysteine at codon 31 of the BRCA2 protein (p.Trp31Cys). The tryptophan residue is highly conserved and there is a large physicochemical difference between tryptophan and cysteine. -

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

Uncertain significance, no assertion criteria provided

clinical testing

Breast Cancer Information Core (BIC) (BRCA2)

-

- -

Hereditary cancer-predisposing syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 31, 2023

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
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

Splicing

Name	Calibrated prediction	Score	Prediction
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

Publications

LitVar

Other links and lift over

dbSNP: rs80359214; hg19: chr13-32893239;