chr13-32363211-C-G

Position:

• chr13-32363211-C-G

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM2 PM5 PP3_Moderate PP5

The NM_000059.4(BRCA2):​c.8009C>G​(p.Ser2670Trp) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 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. S2670L) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: BRCA2 NM_000059.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:4 U:1
• Conservation: PhyloP100: 7.50

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 Likely_pathogenic. Variant got 7 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr13-32363211-C-T is described in Lovd as [Pathogenic].
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.853
• PP5: Variant 13-32363211-C-G is Pathogenic according to our data. Variant chr13-32363211-C-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 489785.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=1, Pathogenic=1, Likely_pathogenic=3}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
BRCA2	NM_000059.4	c.8009C>G	p.Ser2670Trp	missense_variant	18/27	ENST00000380152.8	NP_000050.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
BRCA2	ENST00000380152.8	c.8009C>G	p.Ser2670Trp	missense_variant	18/27	5	NM_000059.4	ENSP00000369497.3
BRCA2	ENST00000530893.7	c.7640C>G	p.Ser2547Trp	missense_variant	18/27	1		ENSP00000499438.2
BRCA2	ENST00000614259.2	n.*67C>G		non_coding_transcript_exon_variant	17/26	2		ENSP00000506251.1
BRCA2	ENST00000614259	n.*67C>G		3_prime_UTR_variant	17/25	2		ENSP00000506251.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:4 Uncertain:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Hereditary cancer-predisposing syndrome Pathogenic:2

Likely pathogenic, criteria provided, single submitter	clinical testing	Ambry Genetics	Nov 16, 2023	The p.S2670W variant (also known as c.8009C>G), located in coding exon 17 of the BRCA2 gene, results from a C to G substitution at nucleotide position 8009. The serine at codon 2670 is replaced by tryptophan, an amino acid with highly dissimilar properties. This amino acid position is highly conserved through mammals but not in all available vertebrate species. RNA studies have shown this variant to result in an incomplete splicing impact, resulting in a transcript which skips exon 17 that is expected to result in loss-of-function (Ambry internal data; Fraile-Bethencourt E et al. Front Genet, 2019 May;10:503; Fraile-Bethencourt E et al. PLoS Genet, 2017 Mar;13:e1006691). This alteration was classified as pathogenic in a multifactorial model of variant interpretation that incorporates co-segregation, family history, co-occurrence, and tumor pathology data (Caputo SM et al. Am J Hum Genet, 2021 Oct;108:1907-1923). This variant was deleterious in a drug sensitivity protein functional assay (Ikegami M et al. Nat Commun, 2020 May;11:2573). Based on internal structural analysis, S2670W is structurally deleterious. The variant is highly destabilizing to the local structure (Yang H et al. Science, 2002 Sep;297:1837-48) In addition, this alteration is predicted to be deleterious by in silico analysis. This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). Based on the majority of available evidence to date, this variant is likely to be pathogenic. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Jun 10, 2022	This missense variant replaces serine with tryptophan at codon 2670 of the BRCA2 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). An RNA study reported that this variant caused leaky out-of-frame skipping of exon 18 in a minigene splicing assay (PMID: 28339459). This variant has been reported in an individual affected with breast cancer and several suspected hereditary breast and ovarian cancer families (PMID: 28664449, 29752822, 34597585). This variant has been observed to cosegregate with disease in multiple families with a likelihood ratio for pathogenicity of 819.97 (PMID: 34597585). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Likely Pathogenic. -

Hereditary breast ovarian cancer syndrome Pathogenic:2

Likely pathogenic, criteria provided, single submitter	curation	German Consortium for Hereditary Breast and Ovarian Cancer, University Hospital Cologne	Apr 09, 2024	According to the ClinGen ENIGMA BRCA2 v1.0.0 criteria we chose these criteria: PM2 (supporting pathogenic): Absent from controls, PP4 (very strong pathogenic): Caputo SM et al., 2021, Combined LR: 7,283.30 , BP4 (supporting benign): BayesDel no-AF score: 0.1593 -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Aug 04, 2023	For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Ser2670 amino acid residue in BRCA2. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 19043619, 23096355, 24735155, 26250392, 29394989). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. Studies have shown that this missense change is associated with altered splicing resulting in unknown protein product impact (PMID: 28339459). Based on a multifactorial likelihood algorithm using genetic, in silico, and/or statistical data, this variant has been determined to have a high probability of being pathogenic (PMID: 34597585). ClinVar contains an entry for this variant (Variation ID: 489785). This missense change has been observed in individual(s) with a personal and/or family history of breast and/or ovarian cancer (PMID: 28664449, 29752822). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces serine, which is neutral and polar, with tryptophan, which is neutral and slightly polar, at codon 2670 of the BRCA2 protein (p.Ser2670Trp). -

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Jan 01, 2024

BRCA2: PM2, PM5, PS4:Moderate, BP1 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.93
BayesDel_addAF	Pathogenic	0.28	D
BayesDel_noAF	Pathogenic	0.16
CADD	Pathogenic	28
DANN	Uncertain	0.99
Eigen	Pathogenic	0.86
Eigen_PC	Pathogenic	0.79
FATHMM_MKL	Pathogenic	0.99	D
M_CAP	Pathogenic	0.36	D
MetaRNN	Pathogenic	0.85	D;D
MetaSVM	Pathogenic	0.80	D
PrimateAI	Uncertain	0.49	T
PROVEAN	Benign	-2.1	N;N
REVEL	Pathogenic	0.82
Sift	Pathogenic	0.0	D;D
Sift4G	Pathogenic	0.0010	D;D
Vest4		0.66
MutPred		0.74		Loss of disorder (P = 1e-04);Loss of disorder (P = 1e-04);
MVP		0.97
MPC		0.18
ClinPred		1.0	D
GERP RS		4.9
gMVP		0.77

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs80359035; hg19: chr13-32937348;