rs80359208

chr13-32394799-A-Gchr13-32394799-A-T

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 4P and 1B. PM1 PP3_Moderate BP6

The NM_000059.4(BRCA2):c.9367A>G(p.Ser3123Gly) variant causes a missense change. The variant allele was found at a frequency of 0.00000547 in 1,461,816 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 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. S3123R) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000055 (0 hom.)
• Consequence: BRCA2 NM_000059.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:2
• Conservation: PhyloP100: 6.06

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 3 ACMG points.

• PM1: In a hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 5 benign, 15 uncertain in NM_000059.4
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.933
• BP6: Variant 13-32394799-A-G is Benign according to our data. Variant chr13-32394799-A-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 52822.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=1, Likely_benign=2}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
BRCA2	NM_000059.4	c.9367A>G	p.Ser3123Gly	missense_variant	25/27	ENST00000380152.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
BRCA2	ENST00000380152.8	c.9367A>G	p.Ser3123Gly	missense_variant	25/27	5	NM_000059.4	A2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.0000159 AC: 4 AN: 251342 Hom.: 0 AF XY: 0.0000221 AC XY: 3 AN XY: 135830

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: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000352

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000547 AC: 8 AN: 1461816 Hom.: 0 Cov.: 31 AF XY: 0.00000550 AC XY: 4 AN XY: 727206

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: 0.00000719

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ExAC AF: 0.00000824 AC: 1

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2 Benign:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

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

Uncertain significance, no assertion criteria provided

clinical testing

Breast Cancer Information Core (BIC) (BRCA2)

May 29, 2002

- -

Hereditary breast ovarian cancer syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Dec 05, 2023

This sequence change replaces serine, which is neutral and polar, with glycine, which is neutral and non-polar, at codon 3123 of the BRCA2 protein (p.Ser3123Gly). This variant is present in population databases (rs80359208, gnomAD 0.004%). This variant has not been reported in the literature in individuals affected with BRCA2-related conditions. ClinVar contains an entry for this variant (Variation ID: 52822). Advanced modeling performed at Invitae incorporating data from internal and/or published experimental studies (PMID: 33609447) indicates that this missense variant is not expected to disrupt BRCA2 function with a negative predictive value of 95%. Experimental studies have shown that this missense change does not substantially affect BRCA2 function (PMID: 29884841, 35736817). 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 Benign:1

Likely benign, criteria provided, single submitter

clinical testing

GeneDx

Feb 11, 2021

Not observed at a significant frequency in large population cohorts (Lek et al., 2016); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 29394989, 32123317, 29884841) -

Hereditary cancer-predisposing syndrome Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Feb 07, 2020

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.15
BayesDel_addAF	Pathogenic	0.17	D
BayesDel_noAF	Uncertain	0.12
Cadd	Pathogenic	27
Dann	Uncertain	1.0
Eigen	Pathogenic	0.80
Eigen_PC	Pathogenic	0.78
FATHMM_MKL	Uncertain	0.96	D
M_CAP	Uncertain	0.16	D
MetaRNN	Pathogenic	0.93	D;D
MetaSVM	Uncertain	0.79	D
MutationTaster	Benign	0.98	D;D
PrimateAI	Benign	0.45	T
PROVEAN	Benign	-1.2	N;N
REVEL	Pathogenic	0.66
Sift	Pathogenic	0.0	D;D
Sift4G	Pathogenic	0.0	D;D
Vest4		0.71
MutPred		0.86		Gain of relative solvent accessibility (P = 0.0479);Gain of relative solvent accessibility (P = 0.0479);
MVP		0.96
MPC		0.16
ClinPred		0.90	D
GERP RS		5.9
gMVP		0.61

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.19		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: rs80359208; hg19: chr13-32968936; COSMIC: COSV101204684; COSMIC: COSV101204684;