rs80358908

chr13-32344558-G-Achr13-32344558-G-Cchr13-32344558-G-T

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP3

The NM_000059.4(BRCA2):c.6842G>A(p.Gly2281Glu) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.00000147 in 1,357,750 control chromosomes in the GnomAD database, with no homozygous occurrence. 2/3 splice prediction tools predicting alterations to normal splicing. 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. G2281V) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000015 (0 hom.)
• Consequence: BRCA2 NM_000059.4 missense, splice_region
• Scores: Splicing: ADA: 0.9992
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:5
• Conservation: PhyloP100: 3.70

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 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF. Scorers claiming Uncertain: max_spliceai. No scorers claiming Benign.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
BRCA2	NM_000059.4	c.6842G>A	p.Gly2281Glu	missense_variant, splice_region_variant	12/27	ENST00000380152.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
BRCA2	ENST00000380152.8	c.6842G>A	p.Gly2281Glu	missense_variant, splice_region_variant	12/27	5	NM_000059.4	A2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000408 AC: 1 AN: 244980 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 133142

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: 0.0000340

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000147 AC: 2 AN: 1357750 Hom.: 0 Cov.: 25 AF XY: 0.00 AC XY: 0 AN XY: 680324

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: 0.0000121

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 9.79e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Alfa AF: 0.000861 Hom.: 0

ExAC AF: 0.00000825 AC: 1

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Hereditary cancer-predisposing syndrome Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	May 30, 2019	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Ambry Genetics	Sep 24, 2021	The c.6842G>A variant (also known as p.G2281E) is located in coding exon 11 of the BRCA2 gene. The glycine at codon 2281 is replaced by glutamic acid, an amino acid with similar properties. This change occurs in the first base pair of coding exon 11, which makes it likely to have some effect on normal mRNA splicing. This nucleotide position is highly conserved in available vertebrate species. In silico splice site analysis predicts that this alteration may weaken the native splice acceptor site. This alteration leads to increased but incomplete skipping of coding exon 11 (also known as exon 12 in the literature; Hujová P et al. Mol Biol Rep, 2019 Jun;46:2877-2884; Meulemans L et al. Cancer Res, 2020 04;80:1374-1386). Complete loss of coding exon 11 retains nearly 50% homology-directed DNA repair activity (Meulemans L et al. Cancer Res, 2020 04;80:1374-1386). However, the clinical impact of loss of exon 11 and to what extent exon 11 is lost is uncertain as a different variant that results in incomplete skipping of coding exon 11 was identified in a compound heterozygous state in a patient without apparent Fanconi Anemia (Li L et al. Hum Mutat, 2009 Nov;30:1543-50). This suggests that exon 11 skipping may be dispensable for clinically relevant function at an unknown threshold of loss (Li L et al. Hum Mutat, 2009 Nov;30:1543-50; Meulemans L et al. Cancer Res, 2020 04;80:1374-1386). This amino acid position is highly conserved in available vertebrate species. In addition, the in silico protein prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

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

Uncertain significance, criteria provided, single submitter

clinical testing

KCCC/NGS Laboratory, Kuwait Cancer Control Center

Nov 13, 2023

This sequence change replaces glycine, which is neutral and non-polar, with glutamic acid, which is acidic and polar, at codon 2281 of the BRCA2 protein (p.Gly2281Glu). Not observed at significant frequency in large population cohorts (gnomAD). In silico analysis supports that this missense variant does not alter protein structure/function. Observed in an individual with breast cancer (Deuitch et al., 2020). This variant is associated with the following publications: (PMID: 32884827).ClinVar contains an entry for this variant (Variation ID: 926077). This nucleotide position is highly conserved . Studies have shown that this missense change results in the activation of a cryptic splice site (PMID: 32046981). 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. -

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Sep 22, 2022

Observed in an individual with breast cancer (Deuitch et al., 2020); In silico analysis supports that this missense variant does not alter protein structure/function; Also known as 7070G>A; Not observed at significant frequency in large population cohorts (gnomAD); In-silico analysis is inconclusive as to whether the variant alters gene splicing. In the absence of RNA/functional studies, the actual effect of this sequence change is unknown.; This variant is associated with the following publications: (PMID: 32884827) -

Hereditary breast ovarian cancer syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Jul 17, 2023

Studies have shown that this missense change results in the activation of a cryptic splice site in 12 (PMID: 32046981). 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. An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. ClinVar contains an entry for this variant (Variation ID: 926077). This variant has not been reported in the literature in individuals affected with BRCA2-related conditions. This variant is present in population databases (rs80358908, gnomAD 0.003%). This sequence change replaces glycine, which is neutral and non-polar, with glutamic acid, which is acidic and polar, at codon 2281 of the BRCA2 protein (p.Gly2281Glu). RNA analysis indicates that this missense change induces altered splicing and likely results in the loss of 1 amino acid residue(s), but is expected to preserve the integrity of the reading-frame. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Pathogenic	0.23	D
BayesDel_noAF	Uncertain	0.090
Cadd	Pathogenic	26
Dann	Uncertain	1.0
Eigen	Uncertain	0.65
Eigen_PC	Uncertain	0.59
FATHMM_MKL	Uncertain	0.94	D
M_CAP	Pathogenic	0.45	D
MetaRNN	Uncertain	0.71	D;D
MetaSVM	Uncertain	0.44	D
MutationTaster	Benign	1.0	D;D
PrimateAI	Benign	0.41	T
PROVEAN	Benign	-1.8	N;N
REVEL	Pathogenic	0.66
Sift	Pathogenic	0.0	D;D
Sift4G	Uncertain	0.0080	D;D
Vest4		0.49
MutPred		0.53		Gain of solvent accessibility (P = 0.0145);Gain of solvent accessibility (P = 0.0145);
MVP		0.95
MPC		0.18
ClinPred		0.96	D
GERP RS		5.0
gMVP		0.32

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.90
SpliceAI score (max)		0.32		Details are displayed if max score is > 0.2
DS_AL_spliceai		0.32		Position offset: 0

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

Publications

LitVar

Other links and lift over

dbSNP: rs80358908; hg19: chr13-32918695;