rs878853614

Positions:

• chr13-32379443-G-A
• chr13-32379443-G-C
• chr13-32379443-G-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.8881G>A​(p.Gly2961Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000342 in 1,461,304 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/19 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. G2961D) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000034 (0 hom.)
• Consequence: BRCA2 NM_000059.4 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:7
• Conservation: PhyloP100: 1.37

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=0.098778605).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
BRCA2	NM_000059.4	c.8881G>A	p.Gly2961Ser	missense_variant	22/27	ENST00000380152.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
BRCA2	ENST00000380152.8	c.8881G>A	p.Gly2961Ser	missense_variant	22/27	5	NM_000059.4	A2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000342 AC: 5 AN: 1461304 Hom.: 0 Cov.: 31 AF XY: 0.00000413 AC XY: 3 AN XY: 726930

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: 0.00000360

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 33

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Nov 18, 2019	Not observed in large population cohorts (Lek 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; Observed in individuals with breast cancer (Cecener 2019); Also known as 9109G>A; This variant is associated with the following publications: (PMID: 31706072, 29310832) -
Uncertain significance, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Nov 07, 2016	Variant summary: The c.8881G>A (p.Gly2961Ser) in BRCA2 gene is a missense change that involves a non-conserved nucleotide and 3/4 in silico tools predict benign outcome. The variant is located within the tower domain, however no functional studies confirming the impact of the variant on the protein function were published at the time of evaluation. The variant is absent from the large control population dataset of ExAC. The variant has not, to our knowledge, been reported in affected individuals in the literature, but was cited as VUS by several reputable databases/clinical laboratories. Lastly, this variant was identified in an internal specimen, undergoing genetic testing, together with c.3228_3229delAG in BRCA1 gene. Taking together, the variant was classified as VUS until more data become available. -

Hereditary cancer-predisposing syndrome Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Ambry Genetics	Jan 26, 2023	The p.G2961S variant (also known as c.8881G>A), located in coding exon 21 of the BRCA2 gene, results from a G to A substitution at nucleotide position 8881. The glycine at codon 2961 is replaced by serine, an amino acid with similar properties. This alteration has been reported in 1/898 unrelated Greek families referred for genetic testing of BRCA1 and BRCA2 and was classified as a variant of unknown significance by the authors (Apessos A et al. Cancer Genet, 2018 01;220:1-12). Another study reported that this alteration was observed in at least one of 603 Turkish patients undergoing BRCA1/2 genetic testing due to their diagnosis of breast cancer (Cecener G et al. Cancer Genet. 2020 Jan;240:23-32). This amino acid position is not well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. 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	May 09, 2023	This missense variant replaces glycine with serine at codon 2961 of the BRCA2 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in an individual affected with breast cancer (PMID: 31706072) and an unaffected individual (PMID: 33471991; Leiden Open Variation Database DB-ID BRCA2_001113). 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. -

Familial cancer of breast Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Baylor Genetics

Nov 30, 2023

- -

Hereditary breast ovarian cancer syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Jan 28, 2024

This sequence change replaces glycine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 2961 of the BRCA2 protein (p.Gly2961Ser). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with breast cancer (PMID: 21520333, 31706072). ClinVar contains an entry for this variant (Variation ID: 236923). 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 with a negative predictive value of 95%. 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. -

Breast carcinoma Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

Medical Genetics Laboratory, Umraniye Training and Research Hospital, University of Health Sciences

Aug 16, 2021

Invasive Ductal Carcinoma -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.086
BayesDel_addAF	Benign	-0.081	T
BayesDel_noAF	Benign	-0.35
CADD	Benign	13
DANN	Uncertain	0.99
Eigen	Benign	-0.93
Eigen_PC	Benign	-0.98
FATHMM_MKL	Benign	0.074	N
M_CAP	Benign	0.062	D
MetaRNN	Benign	0.099	T;T
MetaSVM	Benign	-1.0	T
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.25	T
PROVEAN	Benign	-1.6	N;N
REVEL	Benign	0.088
Sift	Benign	0.15	T;T
Sift4G	Benign	0.54	T;T
Vest4		0.21
MutPred		0.20		Gain of disorder (P = 0.0169);Gain of disorder (P = 0.0169);
MVP		0.81
MPC		0.11
ClinPred		0.47	T
GERP RS		1.0
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: rs878853614; hg19: chr13-32953580;