13-32340237-G-T

Variant names:

• chr13-32340237-G-T
• rs80358820
• NM_000059.4:c.5882G>T

Variant summary

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

The NM_000059.4(BRCA2):​c.5882G>T​(p.Ser1961Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000274 in 1,461,710 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S1961N) has been classified as Benign.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000027 (1 hom.)
• Consequence: BRCA2 NM_000059.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.0500

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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.1431).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
BRCA2	NM_000059.4	c.5882G>T	p.Ser1961Ile	missense_variant	Exon 11 of 27	ENST00000380152.8	NP_000050.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
BRCA2	ENST00000380152.8	c.5882G>T	p.Ser1961Ile	missense_variant	Exon 11 of 27	5	NM_000059.4	ENSP00000369497.3
BRCA2	ENST00000530893.7	c.5513G>T	p.Ser1838Ile	missense_variant	Exon 11 of 27	1		ENSP00000499438.2
BRCA2	ENST00000614259.2	n.5882G>T		non_coding_transcript_exon_variant	Exon 10 of 26	2		ENSP00000506251.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.00000398 AC: 1 AN: 250986 Hom.: 0 AF XY: 0.00000736 AC XY: 1 AN XY: 135800

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000274 AC: 4 AN: 1461710 Hom.: 1 Cov.: 45 AF XY: 0.00000550 AC XY: 4 AN XY: 727152

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: 0.0000464

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ExAC AF: 0.00000824 AC: 1

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Hereditary breast ovarian cancer syndrome Uncertain:1

Aug 23, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces serine, which is neutral and polar, with isoleucine, which is neutral and non-polar, at codon 1961 of the BRCA2 protein (p.Ser1961Ile). 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. This variant has not been reported in the literature in individuals affected with BRCA2-related conditions. This variant is present in population databases (rs80358820, gnomAD 0.003%). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.098
BayesDel_addAF	Benign	-0.21	T
BayesDel_noAF	Benign	-0.44
CADD	Benign	7.4
DANN	Uncertain	0.98
Eigen	Benign	-0.94
Eigen_PC	Benign	-1.0
FATHMM_MKL	Benign	0.11	N
M_CAP	Benign	0.063	D
MetaRNN	Benign	0.14	T;T
MetaSVM	Benign	-0.90	T
PrimateAI	Benign	0.28	T
PROVEAN	Uncertain	-3.8	D;D
REVEL	Benign	0.19
Sift	Uncertain	0.023	D;D
Sift4G	Uncertain	0.031	D;D
Vest4		0.32
MutPred		0.34		Loss of disorder (P = 0.0064);Loss of disorder (P = 0.0064);
MVP		0.85
MPC		0.060
ClinPred		0.080	T
GERP RS		0.15
gMVP		0.23

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		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: rs80358820; hg19: chr13-32914374;