13-32319088-A-G

Variant names:

• chr13-32319088-A-G
• rs80359034
• NM_000059.4:c.79A>G

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 2P and 7B. PM1 BP4_Moderate BP6 BS2

The NM_000059.4(BRCA2):​c.79A>G​(p.Ile27Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000185 in 1,460,468 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign 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. I27M) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.000018 (2 hom.)
• Consequence: BRCA2 NM_000059.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:9 B:5
• Conservation: PhyloP100: 0.353
• Publications: 19 publications found

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 Gene-Disease associations (from GenCC):

• breast-ovarian cancer, familial, susceptibility to, 2

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Ambry Genetics, Genomics England PanelApp, Labcorp Genetics (formerly Invitae), ClinGen
• Fanconi anemia complementation group D1

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics, ClinGen, G2P
• pancreatic cancer, susceptibility to, 2

  Inheritance: AD Classification: STRONG Submitted by: Genomics England PanelApp
• sarcoma

  Inheritance: AD Classification: MODERATE Submitted by: Genomics England PanelApp
• hereditary breast ovarian cancer syndrome

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• Fanconi anemia

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• medulloblastoma

  Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics

ACMG classification

Our verdict: Likely_benign. The variant received -5 ACMG points.

• PM1: In a hotspot region, there are 7 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 2 benign, 38 uncertain in NM_000059.4
• BP4: Computational evidence support a benign effect (MetaRNN=0.12545416).
• BP6: Variant 13-32319088-A-G is Benign according to our data. Variant chr13-32319088-A-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 52467.
• BS2: High Homozygotes in GnomAdExome4 at 2 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
BRCA2	NM_000059.4	c.79A>G	p.Ile27Val	missense_variant	Exon 3 of 27	ENST00000380152.8	NP_000050.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
BRCA2	ENST00000380152.8	c.79A>G	p.Ile27Val	missense_variant	Exon 3 of 27	5	NM_000059.4	ENSP00000369497.3
BRCA2	ENST00000614259.2	n.79A>G		non_coding_transcript_exon_variant	Exon 2 of 26	2		ENSP00000506251.1
BRCA2	ENST00000530893.7	c.-291A>G		5_prime_UTR_variant	Exon 3 of 27	1		ENSP00000499438.2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD2 exomes AF: 0.00000799 AC: 2 AN: 250402 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000290

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000882

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000185 AC: 27 AN: 1460468 Hom.: 2 Cov.: 32 AF XY: 0.0000138 AC XY: 10 AN XY: 726588

African (AFR) AF: 0.00 AC: 0 AN: 33406

American (AMR) AF: 0.0000224 AC: 1 AN: 44704

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26124

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39676

South Asian (SAS) AF: 0.00 AC: 0 AN: 86174

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53366

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5752

European-Non Finnish (NFE) AF: 0.0000207 AC: 23 AN: 1110920

Other (OTH) AF: 0.0000331 AC: 2 AN: 60346

GnomAD4 genome Cov.: 33

Alfa AF: 0.0000340 Hom.: 0

Bravo AF: 0.00000378

ExAC AF: 0.00000824 AC: 1

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:9 Benign:5

Revision: criteria provided, conflicting classifications

Submissions by phenotype

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

Mar 09, 2010

Sharing Clinical Reports Project (SCRP)

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

Feb 20, 2004

Breast Cancer Information Core (BIC) (BRCA2)

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

Mar 02, 2020

BRCAlab, Lund University

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

not provided Uncertain:2 Benign:1

Nov 15, 2019

Quest Diagnostics Nichols Institute San Juan Capistrano

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Feb 22, 2021

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Observed in individuals with melanoma, breast, ovarian, or pancreatic cancers, one of whom also carried a pathogenic BRCA2 variant however phase was unknown (Bartsch 2010, Sanz 2010, Azzollini 2016, Caleca 2018, Santonocito 2020, Wai 2020); Published functional studies demonstrate no damaging effect: similar to wild type in homologous recombination and double-strand break repair (HR/DSBR) activity, inhibition of HR/DSBR activity with over-expression, PALB2 binding activity, and nuclear localization (Xia 2006, Caleca 2018); In silico analysis supports that this missense variant does not alter protein structure/function; In silico analysis, which includes splice predictors and evolutionary conservation, suggests this variant may impact gene splicing, however splicing studies demonstrate mixed results (Pettigrew 2008, Sanz 2010, Tubeuf 2020); Not observed at a significant frequency in large population cohorts (Lek 2016); Also known as 307A>G; This variant is associated with the following publications: (PMID: 32438681, 24323938, 20041885, 17899372, 27062684, 32123317, 30410870, 16793542, 32641407, 20215541)

Jan 02, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Hereditary cancer-predisposing syndrome Uncertain:1 Benign:1

Aug 02, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.I27V variant (also known as c.79A>G), located in coding exon 2 of the BRCA2 gene, results from an A to G substitution at nucleotide position 79. The isoleucine at codon 27 is replaced by valine, an amino acid with highly similar properties. This alteration was reported in a proband diagnosed with melanoma whose father had pancreatic cancer; both the proband and his father carried the alteration, as did an unaffected uncle (Bartsch DK et al. Clin Genet. 2010 Apr; 77(4):333-41). Authors reported that it was unclear if this alteration was linked with disease. This alteration was also reported in multiple individuals diagnosed with breast and/or ovarian cancer (Azzollini J et al. Eur J Intern Med, 2016 Jul;32:65-71; Santonocito C et al. Cancers (Basel), 2020 May;12:). One study looked at exonic splicing enhancers using an in silico model to predict which variants may affect splicing and this alteration was predicted to have an increased effect on exonic splicing enhancers; authors reported this may adversely affect splicing but further functional studies are needed (Pettigrew CA et al. Breast Cancer Res Treat. 2008 Jul; 110(2):227-34). In another study, this alteration had activity similar to wildtype in a PALB2 binding assay and a homologous recombination assay (Xia B et al. Mol Cell. 2006 Jun; 22(6):719-29). This amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.

May 24, 2016

Color Diagnostics, LLC DBA Color Health

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Malignant tumor of breast Uncertain:1

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

Familial cancer of breast Uncertain:1

Oct 24, 2023

Baylor Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Hereditary breast ovarian cancer syndrome Uncertain:1

Jan 30, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces isoleucine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 27 of the BRCA2 protein (p.Ile27Val). This variant is present in population databases (rs80359034, gnomAD 0.002%). This missense change has been observed in individual(s) with a personal and/or family history of melanoma, pancreatic, breast and/or ovarian cancer (PMID: 20041885, 27062684, 32438681). This variant is also known as 307A>G. ClinVar contains an entry for this variant (Variation ID: 52467). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is not expected to disrupt BRCA2 protein function with a negative predictive value of 95%. Experimental studies have shown that this missense change does not substantially affect BRCA2 function (PMID: 16793542, 24323938, 32641407). RNA analysis performed to evaluate the impact of this missense change on mRNA splicing indicates it does not significantly alter splicing (PMID: 20215541, 22505045; internal data). 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 specified Benign:1

Feb 26, 2024

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: BRCA2 c.79A>G (p.Ile27Val) results in a conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 8e-06 in 250402 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.79A>G has been reported in the literature in individuals affected with Hereditary Breast And Ovarian Cancer Syndrome, without strong evidence for causality (example, Houdayer_2012, Bartsch_2010). These report(s) do not provide unequivocal conclusions about association of the variant with Hereditary Breast And Ovarian Cancer Syndrome. Co-occurrences with other pathogenic variant(s) have been reported (BRCA2 c.631G>A p.Val211Ile and c.7008-2A>T in one patient with Ovarian Cancer), providing supporting evidence for a benign role (Santonocito_2020). Multiple publications report experimental evidence evaluating an impact on protein function. These results showed no damaging effect of this variant using mESC complementation and HDR assay (example, Xia_2006, Caleca_2018, Thomassen_2022). The following publications have been ascertained in the context of this evaluation (PMID: 20041885, 24323938, 22505045, 19609323, 17899372, 32438681, 20215541, 35979650, 16793542). ClinVar contains an entry for this variant (Variation ID: 52467). Based on the evidence outlined above, the variant was classified as likely benign.

BRCA2-related cancer predisposition Benign:1

Apr 25, 2024

All of Us Research Program, National Institutes of Health

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

BRCA2-related disorder Benign:1

May 22, 2024

PreventionGenetics, part of Exact Sciences

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.068
BayesDel_addAF	Benign	-0.22	T
BayesDel_noAF	Benign	-0.54
CADD	Benign	8.3
DANN	Uncertain	1.0
DEOGEN2	Benign	0.0	.;.
Eigen	Benign	-0.50
Eigen_PC	Benign	-0.34
FATHMM_MKL	Benign	0.75	D
LIST_S2	Benign	0.0	.;.
M_CAP	Benign	0.039	D
MetaRNN	Benign	0.13	T;T
MetaSVM	Benign	-0.93	T
MutationAssessor	Benign	0.0	.;.
PhyloP100		0.35
PrimateAI	Benign	0.30	T
PROVEAN	Benign	-0.24	N;N
REVEL	Benign	0.057
Sift	Benign	0.073	T;T
Sift4G	Benign	0.070	T;T
Vest4		0.26
ClinPred		0.68	D
GERP RS		3.2
gMVP		0.23
Mutation Taster		=95/5	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
Splicevardb		1.0
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

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

Other links and lift over

dbSNP: rs80359034; hg19: chr13-32893225;