13-32362645-C-T

Position:

• chr13-32362645-C-T

Variant summary

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

The NM_000059.4(BRCA2):​c.7928C>T​(p.Ala2643Val) variant causes a missense change. The variant allele was found at a frequency of 0.0000246 in 1,461,872 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.000025 (0 hom.)
• Consequence: BRCA2 NM_000059.4 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:9
• Conservation: PhyloP100: 4.07

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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
BRCA2	NM_000059.4	c.7928C>T	p.Ala2643Val	missense_variant	17/27	ENST00000380152.8	NP_000050.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
BRCA2	ENST00000380152.8	c.7928C>T	p.Ala2643Val	missense_variant	17/27	5	NM_000059.4	ENSP00000369497.3
BRCA2	ENST00000530893.7	c.7559C>T	p.Ala2520Val	missense_variant	17/27	1		ENSP00000499438.2
BRCA2	ENST00000614259.2	n.7936C>T		non_coding_transcript_exon_variant	16/26	2		ENSP00000506251.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.0000246 AC: 36 AN: 1461872 Hom.: 0 Cov.: 33 AF XY: 0.0000234 AC XY: 17 AN XY: 727236

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000315

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:9

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Uncertain:3

Uncertain significance, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Jul 12, 2018	- -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Jun 16, 2020	Identified in an unaffected control but absent from breast cancer cases (Wen 2018); Not observed in large population cohorts (Lek 2016); In silico analysis supports that this missense variant does not alter protein structure/function; Also known as 8156C>T; This variant is associated with the following publications: (PMID: 28993434, 19043619, 24817641) -
Uncertain significance, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Dec 05, 2016	Variant summary: The BRCA2 c.7928C>T (p.Ala2643Val) variant involves the alteration of a conserved nucleotide. 3/4 in silico tools predict a damaging outcome for this substitution (SNPs&GO not captured due to low reliability index). This variant is absent in 121376 control chromosomes. The variant of interest has not, to our knowledge, been reported in affected individuals via; nor evaluated for functional impact by in vivo/vitro studies. Multiple clinical diagnostic laboratories/reputable databases classified this variant as uncertain significance. Because of the absence of clinical information and the lack of functional studies, the variant is classified as a variant of uncertain significance (VUS) until additional information becomes available. -

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

Uncertain significance, no assertion criteria provided	clinical testing	Sharing Clinical Reports Project (SCRP)	May 17, 2012	- -
Uncertain significance, no assertion criteria provided	clinical testing	Breast Cancer Information Core (BIC) (BRCA2)	-	- -

Hereditary cancer-predisposing syndrome Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Ambry Genetics	Dec 15, 2023	The p.A2643V variant (also known as c.7928C>T), located in coding exon 16 of the BRCA2 gene, results from a C to T substitution at nucleotide position 7928. The alanine at codon 2643 is replaced by valine, an amino acid with similar properties. This alteration was identified in an individual diagnosed with bone marrow failure (Przychodzen B et al. Oncotarget, 2018 Jan;9:2050-2057). Additionally, this alteration has been detected in 0/2575 unselected patients with breast cancer and 1/2809 healthy control individuals from a Malaysian cohort (Wen WX et al. J. Med. Genet. 2018 02;55(2):97-103). This amino acid position is well 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. -
Uncertain significance, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Jul 30, 2021	This missense variant replaces alanine with valine at codon 2643 of the BRCA2 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in one unaffected individual in a breast cancer case-control study (PMID: 28993434, 33471991) and a family history likelihood ratio for pathogenicity of 0.6668 (PMID: 31131967). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. -

BRCA2-related cancer predisposition Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

All of Us Research Program, National Institutes of Health

Jul 10, 2024

This missense variant replaces alanine with valine at codon 2643 of the BRCA2 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in one unaffected individual in a breast cancer case-control study (PMID: 28993434, 33471991) and a family history likelihood ratio for pathogenicity of 0.6668 (PMID: 31131967). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. -

Hereditary breast ovarian cancer syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Sep 23, 2023

This variant is not present in population databases (gnomAD no frequency). 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: 91498). This missense change has been observed in individual(s) with breast cancer (PMID: 10923033). This sequence change replaces alanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 2643 of the BRCA2 protein (p.Ala2643Val). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.70
BayesDel_addAF	Pathogenic	0.23	D
BayesDel_noAF	Uncertain	0.10
CADD	Uncertain	24
DANN	Pathogenic	1.0
Eigen	Pathogenic	0.82
Eigen_PC	Pathogenic	0.79
FATHMM_MKL	Uncertain	0.89	D
M_CAP	Uncertain	0.19	D
MetaRNN	Uncertain	0.67	D;D
MetaSVM	Uncertain	0.65	D
PrimateAI	Uncertain	0.49	T
PROVEAN	Benign	-1.1	N;N
REVEL	Uncertain	0.58
Sift	Uncertain	0.0010	D;D
Sift4G	Uncertain	0.0040	D;D
Vest4		0.51
MutPred		0.74		Gain of ubiquitination at K2640 (P = 0.0719);Gain of ubiquitination at K2640 (P = 0.0719);
MVP		0.94
MPC		0.17
ClinPred		0.88	D
GERP RS		5.7
gMVP		0.43

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: rs80359018; hg19: chr13-32936782;