rs80359034

Positions:

Variant summary

Our verdict is Benign. Variant got -7 ACMG points: 0P and 7B. BP4_ModerateBP6BS2

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. 13/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.000018 ( 2 hom. )

Consequence

BRCA2
NM_000059.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:9B:4

Conservation

PhyloP100: 0.353

Variant links:

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -7 ACMG points.

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 id is 52467.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Benign=2, Uncertain_significance=5}.

BS2

High Homozygotes in GnomAdExome4 at 2 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
BRCA2	NM_000059.4 linkuse as main transcript	c.79A>G	p.Ile27Val	missense_variant	3/27	ENST00000380152.8	NP_000050.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
BRCA2	ENST00000380152.8 linkuse as main transcript	c.79A>G	p.Ile27Val	missense_variant	3/27	5	NM_000059.4	ENSP00000369497	A2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000799

AC:

AN:

250402

Hom.:

AF XY:

0.00

AC XY:

AN XY:

135670

show subpopulations

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 SAS 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:

AN:

1460468

Hom.:

Cov.:

AF XY:

0.0000138

AC XY:

AN XY:

726588

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000224

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000207

Gnomad4 OTH exome

AF:

0.0000331

GnomAD4 genome

Cov.:

Alfa

AF:

0.0000282

Hom.:

Bravo

AF:

0.00000378

ExAC

AF:

0.00000824

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:9Benign:4

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Breast-ovarian cancer, familial, susceptibility to, 2

Uncertain:3Benign:1

Uncertain significance, no assertion criteria provided	clinical testing	Breast Cancer Information Core (BIC) (BRCA2)	Feb 20, 2004	- -
Uncertain significance, no assertion criteria provided	clinical testing	Sharing Clinical Reports Project (SCRP)	Mar 09, 2010	- -
Uncertain significance, no assertion criteria provided	clinical testing	BRCAlab, Lund University	Mar 02, 2020	- -
Benign, criteria provided, single submitter	clinical testing	All of Us Research Program, National Institutes of Health	Dec 01, 2023	- -

not provided

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Feb 22, 2021	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) -
Uncertain significance, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Nov 15, 2019	- -

Hereditary cancer-predisposing syndrome

Uncertain:1Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Ambry Genetics	Aug 02, 2023	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. -
Benign, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	May 24, 2016	- -

Malignant tumor of breast

Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

Department of Pathology and Laboratory Medicine, Sinai Health System

- -

Familial cancer of breast

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Baylor Genetics

Oct 24, 2023

- -

Hereditary breast ovarian cancer syndrome

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 26, 2024

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). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae 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). 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

Likely benign, criteria provided, single submitter

clinical testing

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

Feb 26, 2024

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 disorder

Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

May 22, 2024

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

BayesDel_noAF

Benign

-0.54

CADD

Benign

8.3

DANN

Uncertain

1.0

Eigen

Benign

-0.50

Eigen_PC

Benign

-0.34

FATHMM_MKL

Benign

0.75

M_CAP

Benign

0.039

MetaRNN

Benign

0.13

T;T

MetaSVM

Benign

-0.93

MutationTaster

Benign

0.99

N;N

PrimateAI

Benign

0.30

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

MutPred

0.18

Loss of catalytic residue at I27 (P = 0.0823);Loss of catalytic residue at I27 (P = 0.0823);

MVP

0.72

MPC

0.084

ClinPred

0.68

GERP RS

3.2

gMVP

0.23

Splicing

Name

Calibrated prediction

Score

Prediction

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over