rs80358702

Positions:

• chr13-32326150-G-A
• chr13-32326150-G-C

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM2 PP5_Very_Strong

The NM_000059.4(BRCA2):​c.475G>A​(p.Val159Met) variant causes a missense, splice region change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Likely pathogenic (★★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: BRCA2 NM_000059.4 missense, splice_region
• Scores: Splicing: ADA: 0.9997
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:12
• Conservation: PhyloP100: 3.81

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 Pathogenic. Variant got 10 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 13-32326150-G-A is Pathogenic according to our data. Variant chr13-32326150-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 51711.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr13-32326150-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
BRCA2	NM_000059.4	c.475G>A	p.Val159Met	missense_variant, splice_region_variant	5/27	ENST00000380152.8	NP_000050.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
BRCA2	ENST00000380152.8	c.475G>A	p.Val159Met	missense_variant, splice_region_variant	5/27	5	NM_000059.4	ENSP00000369497.3
BRCA2	ENST00000530893.7	c.106G>A	p.Val36Met	missense_variant, splice_region_variant	5/27	1		ENSP00000499438.2
BRCA2	ENST00000614259.2	n.475G>A		splice_region_variant, non_coding_transcript_exon_variant	4/26	2		ENSP00000506251.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:12

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Breast-ovarian cancer, familial, susceptibility to, 2 Pathogenic:3

Pathogenic, no assertion criteria provided	clinical testing	Breast Cancer Information Core (BIC) (BRCA2)	Sep 27, 2005	- -
Pathogenic, criteria provided, single submitter	clinical testing	Genetics and Molecular Pathology, SA Pathology	Aug 13, 2021	- -
Pathogenic, criteria provided, single submitter	clinical testing	Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge	Oct 02, 2015	- -

not provided Pathogenic:3

Likely pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Oct 11, 2022	Not observed at significant frequency in large population cohorts (gnomAD); Exonic splice variant demonstrated to result in aberrant splicing, leading to an abnormal message that is subject to nonsense-mediated mRNA decay or to an abnormal protein product (Machackova et al., 2008); In silico analysis supports a deleterious effect on splicing; In silico analysis supports that this missense variant does not alter protein structure/function; Also known as 703G>A; This variant is associated with the following publications: (PMID: 24312913, 22798144, 25863477, 28008555, 29387975, 28111427, 31589614, 32444794, 30322717, 31911673, 33050356, 29446198, 33471991, 18489799) -
Likely pathogenic, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Jul 07, 2023	The BRCA2 c.475G>A (p.Val159Met) variant has been reported in the published literature in individuals affected with breast/ovarian cancer (PMIDs: 22798144 (2012), 28008555 (2017), 30322717 (2018), 33471991 (2021), see also LOVD (http://databases.lovd.nl/shared/)). The variant was also reported to be enriched in a cohort of Korean breast/ovarian cancer patients (PMID: 28111427 (2017)). Another study reported that this variant interferes with proper BRCA2 mRNA splicing and causes exon skipping in two unrelated breast cancer patients, though the authors could not determine if any full length transcript was produced (PMID: 18489799 (2008)). This variant has not been reported in large, multi-ethnic general populations (Genome Aggregation Database, http://gnomad.broadinstitute.org). Analysis of this variant using software algorithms for the prediction of the effect of nucleotide changes on splicing yielded predictions that this variant may affect proper BRCA2 mRNA splicing. Based on the available information, this variant is classified as likely pathogenic. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	Oct 23, 2020	- -

Hereditary cancer-predisposing syndrome Pathogenic:3

Likely pathogenic, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Jul 06, 2021	This variant causes a G>A nucleotide substitution in the last nucleotide of exon 5 in the BRCA2 gene. This variant is predicted to disrupt splicing at the intron 5 splice donor site and an RNA study have shown that this variant causes skipping of exon 5, resulting in premature truncation (PMID: 18489799). This variant is reported to have comparable sensitivity to PARP-inhibitors as wildtype (PMID: 32444794). This variant has been observed in females affected with breast and/or ovarian cancer (PMID: 18489799, 25863477, 28111427) and an individual affected with male breast cancer (PMID: 28008555). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Loss of BRCA2 function is a known mechanism of disease. Based on the available evidence, this variant is classified as Likely Pathogenic. -
Likely pathogenic, criteria provided, single submitter	curation	Sema4, Sema4	Oct 22, 2021	- -
Pathogenic, criteria provided, single submitter	clinical testing	Ambry Genetics	Jul 22, 2023	The c.475G>A pathogenic variant (also known as p.V159M), located in coding exon 4 of the BRCA2 gene, results from a G to A substitution at nucleotide position 475. The amino acid change results in valine to methionine at codon 159, an amino acid with highly similar properties. This alteration has been reported in multiple breast and/or ovarian cancer cohorts (Kim H et al. Breast Cancer Res. Treat. 2012 Aug; 134(3):1315-26; Park JS et al. Cancer Res Treat. 2017 Jan; Pritzlaff M et al. Breast Cancer Res. Treat. 2017 Feb;161:575-586). This change occurs in the last base pair of coding exon 4, which makes it likely to have some effect on normal mRNA splicing and RNA studies have demonstrated that this alteration results in abnormal splicing in the set of samples tested (Ambry internal data; Machackova E et al. BMC Cancer. 2008; 8:140). In silico splice site analysis predicts that this alteration will weaken the native splice donor site. Based on the majority of available evidence to date, this alteration is interpreted as a disease-causing mutation. -

Carcinoma of pancreas Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

CZECANCA consortium

Mar 04, 2021

- -

Familial cancer of breast Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Baylor Genetics

Feb 10, 2023

- -

Hereditary breast ovarian cancer syndrome Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Aug 08, 2023

Experimental studies have shown that this missense change does not substantially affect BRCA2 function (PMID: 32444794). 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: 51711). This missense change has been observed in individual(s) with hereditary breast and ovarian cancer syndrome (PMID: 18489799, 25863477, 29446198). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces valine, which is neutral and non-polar, with methionine, which is neutral and non-polar, at codon 159 of the BRCA2 protein (p.Val159Met). RNA analysis indicates that this missense change induces altered splicing and may result in an absent or disrupted protein product. Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Studies have shown that this missense change results in skipping of exon 5 and introduces a premature termination codon (PMID: 18489799). The resulting mRNA is expected to undergo nonsense-mediated decay. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Benign	-0.015	T
BayesDel_noAF	Benign	-0.26
CADD	Pathogenic	33
DANN	Uncertain	1.0
Eigen	Uncertain	0.21
Eigen_PC	Benign	0.20
FATHMM_MKL	Benign	0.75	D
M_CAP	Uncertain	0.15	D
MetaRNN	Benign	0.39	T;T
MetaSVM	Benign	-0.93	T
PrimateAI	Benign	0.45	T
PROVEAN	Benign	-0.76	N;N
REVEL	Benign	0.16
Sift	Uncertain	0.011	D;D
Sift4G	Uncertain	0.050	T;T
Vest4		0.56
MutPred		0.24		Gain of ubiquitination at K157 (P = 0.0638);Gain of ubiquitination at K157 (P = 0.0638);
MVP		0.88
MPC		0.16
ClinPred		0.85	D
GERP RS		4.1
gMVP		0.18

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	1.0
SpliceAI score (max)		0.75		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.75		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: rs80358702; hg19: chr13-32900287;