rs80358702

Variant names:

• chr13-32326150-G-A
• rs80358702
• NM_000059.4:c.475G>A

Your query was ambiguous. Multiple possible variants found:

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

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PM2 PP3 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]

ACMG classification

Verdict is Pathogenic. Variant got 11 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, max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.
• 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 rank	MANE	Protein	UniProt
BRCA2	NM_000059.4	c.475G>A	p.Val159Met	missense_variant, splice_region_variant	Exon 5 of 27	ENST00000380152.8	NP_000050.3

Ensembl

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

Sep 27, 2005

Breast Cancer Information Core (BIC) (BRCA2)

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Oct 02, 2015

Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Aug 13, 2021

Genetics and Molecular Pathology, SA Pathology

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Pathogenic:3

Jul 07, 2023

Quest Diagnostics Nichols Institute San Juan Capistrano

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Oct 23, 2020

Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Oct 11, 2022

GeneDx

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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) -

Hereditary cancer-predisposing syndrome Pathogenic:3

Oct 22, 2021

Sema4, Sema4

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: curation

- -

Jul 22, 2023

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Jul 11, 2024

Color Diagnostics, LLC DBA Color Health

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant substitutes a conserved guanine with an adenine at the last nucleotide of exon 5 in the BRCA2 gene. An RNA study has reported that this variant in two unrelated carriers resulted in the out-of-frame skipping of exon 5, although whether this variant transcript produced any full-length transcripts could not be determined (PMID: 18489799). Furthermore, this variant and a similar c.475G>C change both have been reported to cause the skipping of exon 5 or an unspecified splicing defect (ClinVar accession: SCV000275357.8, SCV004310835.1). Exon 5 skipping is expected to result in an absent or nonfunctional protein product. This variant has been reported in at least one individual affected with ovarian cancer, two individuals affected with breast cancer (PMID: 22798144, 25863477, 28008555, 30322717, 33471991) and in suspected hereditary breast and ovarian cancer families (PMID: 18489799, 28111427, 29446198). A multifactorial analysis has reported a likelihood ratio for pathogenicity based on personal and family history of approximately 19.57 (from report log(LR) = 1.29151535) (PMID: 31853058). 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. -

Carcinoma of pancreas Pathogenic:1

Mar 04, 2021

CZECANCA consortium

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Familial cancer of breast Pathogenic:1

Feb 10, 2023

Baylor Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Hereditary breast ovarian cancer syndrome Pathogenic:1

Oct 31, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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 altered protein product. This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with hereditary breast and ovarian cancer syndrome (PMID: 18489799, 25863477, 29446198). ClinVar contains an entry for this variant (Variation ID: 51711). 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. Experimental studies have shown that this missense change does not substantially affect BRCA2 function (PMID: 32444794). 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 produces a non-functional protein and/or introduces a premature termination codon (PMID: 18489799). This variant disrupts the c.475G nucleotide in the BRCA2 gene. Other variant(s) that disrupt this nucleotide have been determined to be pathogenic (internal data). This suggests that this nucleotide is clinically significant, and that variants that disrupt this position are likely to be disease-causing. 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;