rs80359187

Positions:

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM2PP3_StrongPP5_Very_Strong

The NM_000059.4(BRCA2):c.9227G>A(p.Gly3076Glu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,518 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

BRCA2
NM_000059.4 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:8U:2

Conservation

PhyloP100: 9.00

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:

BRCA2 (HGNC:):

BRCA2 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 14 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.982

PP5

Variant 13-32380116-G-A is Pathogenic according to our data. Variant chr13-32380116-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 52780.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr13-32380116-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
BRCA2	NM_000059.4 linkuse as main transcript	c.9227G>A	p.Gly3076Glu	missense_variant	24/27	ENST00000380152.8	NP_000050.3	P51587

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
BRCA2	ENST00000380152.8 linkuse as main transcript	c.9227G>A	p.Gly3076Glu	missense_variant	24/27	5	NM_000059.4	ENSP00000369497.3	P51587
BRCA2	ENST00000530893.7 linkuse as main transcript	c.8858G>A	p.Gly2953Glu	missense_variant	24/27	1		ENSP00000499438.2	A0A590UJI7
BRCA2	ENST00000614259.2 linkuse as main transcript	n.*1285G>A		non_coding_transcript_exon_variant	23/26	2		ENSP00000506251.1	A0A7P0TAP7
BRCA2	ENST00000614259.2 linkuse as main transcript	n.*1285G>A		3_prime_UTR_variant	23/26	2		ENSP00000506251.1	A0A7P0TAP7

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000398

AC:

AN:

250980

Hom.:

AF XY:

0.00000737

AC XY:

AN XY:

135654

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

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:

0.00000881

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

6.84e-7

AC:

AN:

1461518

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

727032

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

8.99e-7

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ExAC

AF:

0.00000824

AC:

EpiCase

AF:

0.00

EpiControl

AF:

0.0000593

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:8Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Pathogenic:3

Likely pathogenic, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Oct 02, 2019	The BRCA2 c.9227G>A; p.Gly3076Glu variant (rs80359187) is reported in the literature in multiple individuals with a personal and/or family history of breast, ovarian, and/or pancreatic cancer (Alemar 2017, Hahn 2003, Ikeda 2001, Li 2018). In one family, this variant segregated with disease in at least three affected family members (Hahn 2003). This variant is found on a single chromosome in the Genome Aggregation Database (1/250980 alleles), indicating it is not a common polymorphism. The glycine at codon 3076 is highly conserved, and functional analyses indicate decreased activity in assays of homology-directed recombination (HDR) (Guidugli 2013, Guidugli 2018). Additionally, other amino acid substitutions at this codon (p.Gly3076Arg, p.Gly3076Val) exhibit decreased HDR activity (Guidugli 2018), and p.Gly3076Val has been reported in a cohort of individuals with breast and/or ovarian cancer (Alemar 2017); however, the clinical significance of other variants at the same codon has not been conclusively determined. Still, based on available information, the p.Gly3076Glu variant is considered to be likely pathogenic. References: Alemar B et al. BRCA1 and BRCA2 mutational profile and prevalence in hereditary breast and ovarian cancer (HBOC) probands from Southern Brazil: Are international testing criteria appropriate for this specific population? PLoS One. 2017 Nov 21;12(11):e0187630. Guidugli L et al. A classification model for BRCA2 DNA binding domain missense variants based on homology-directed repair activity. Cancer Res. 2013 Jan 1;73(1):265-75. Guidugli L et al. Assessment of the Clinical Relevance of BRCA2 Missense Variants by Functional and Computational Approaches. Am J Hum Genet. 2018 Feb 1;102(2):233-248. Hahn SA et al. BRCA2 germline mutations in familial pancreatic carcinoma. J Natl Cancer Inst. 2003 Feb 5;95(3):214-21. Ikeda N et al. Frequency of BRCA1 and BRCA2 germline mutations in Japanese breast cancer families. Int J Cancer. 2001 Jan 1;91(1):83-8. Li A et al. BRCA germline mutations in an unselected nationwide cohort of Chinese patients with ovarian cancer and healthy controls. Gynecol Oncol. 2018 Oct;151(1):145-152. -
Likely pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Jan 05, 2024	In silico analysis supports that this missense variant does not alter protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); Also known as 9455G>A; This variant is associated with the following publications: (PMID: 19043619, 11149425, 19064968, 20195775, 18437078, 12569143, 23108138, 26402249, 28324225, 24323938, 22711857, 29161300, 29394989, 26295337, 12228710, 22632462, 29884841, 30113427, 35736817, 35665744, 35563554, 33609447, 34906479, 30078507, 29922827, 30040829, 28888541) -
Pathogenic, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	May 08, 2024	The BRCA2 c.9227G>A (p.Gly3076Glu) variant has been reported in the published literature in individuals with breast and/or ovarian cancer or pancreatic cancer (PMIDs: 11149425 (2001), 12569143 (2003), 20195775 (2010), 22711857 (2012), 28324225 (2017), 28888541 (2017), 30078507 (2018), and 30040829 (2018)). Experimental studies showed that this variant results in decreased activity in homology-directed recombination (HDR) assays (PMIDs: 23108138 (2013), 29394989 (2018), 29884841 (2019), 33609447 (2021), and 35736817 (2022)). In addition, a multifactorial likelihood analysis predicted the variant to be likely deleterious (PMID: 19043619 (2008)). The frequency of this variant in the general population, 0.000004 (1/250980 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is uninformative in the assessment of its pathogenicity. Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded predictions that this variant is damaging. Based on the available information, this variant is classified as pathogenic. -

Breast-ovarian cancer, familial, susceptibility to, 2

Pathogenic:1Uncertain:2

Uncertain significance, flagged submission	clinical testing	Counsyl	Sep 11, 2016	- -
Uncertain significance, flagged submission	clinical testing	Breast Cancer Information Core (BIC) (BRCA2)	Jul 10, 1998	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Genetics and Molecular Pathology, SA Pathology	Apr 03, 2020	The BRCA2 c.9227G>A variant is classified as Likely Pathogenic (PS3, PM2, PP5) The BRCA2 c.9227G>A variant is a single nucleotide change the BRCA2 gene, which is predicted to change the amino acid glycine at position 3076 in the protein to glutamic acid. The variant is rare in population databases (PM2). not in FLOSSIES - very rare 1 in 250000 alleles. Well-established functional studies show a deleterious effect of this variant (PS3). Invariantly conserved (to Class Echinodermata; Strongylocentrotus purpuratus) and in known functional domain Yang et al., 2002 PMID:12228710. no impact on splicing The variant has been reported in dbSNP (rs80359187) and has been reported with Conflicting interpretations of pathogenicity by other diagnostic laboratories (ClinVar Variation ID: 52780). It has not been reported in HGMD. -

Hereditary breast ovarian cancer syndrome

Pathogenic:2

Likely pathogenic, criteria provided, single submitter	curation	Cancer Variant Interpretation Group UK, Institute of Cancer Research, London	Oct 09, 2018	Data used in classification: The frequency of this variant is 1/122,925 individuals (gnomAD) (PM2_mod). This variant is predicted deleterious on AlignGVGD (class: C65), SIFT (Deleterious), Polyphen2 HumVar (probably damaging) and CADD (27.7) (PP3_sup). The variant is in the DNA-binding domain of BRCA2 (PM1_sup). In the BRCA2 Homology-Directed Repair Activity assay for the DNA Binding Domain (Guidugli et al Cancer Res 2013;73:265-275,Couch Lab), the variant has a probability of pathogenicity of 1.0 (PS3_strong). This variant is classified as likely pathogenic by 2 submitters on ClinVar; accredited USA diagnostic laboratories Ambry Genetics and GeneDx, both classified in 2017 (PP5_sup). Data not used in classification: There are additional reports of this variant in ClinVar (3), BIC (2), and BRCA2 LOVD (1). -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Mar 19, 2022	For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Gly3076 amino acid residue in BRCA2. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 23108138, 29394989, 30254663, 32814805). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. Experimental studies have shown that this missense change affects BRCA2 function (PMID: 19043619, 23108138, 29394989). Advanced modeling of experimental studies (such as gene expression, population dynamics, functional pathways, and cell-cycle effects in cell culture) performed at Invitae indicates that this missense variant is expected to disrupt BRCA2 protein function. ClinVar contains an entry for this variant (Variation ID: 52780). This missense change has been observed in individual(s) with breast, ovarian, and/or pancreatic cancer (PMID: 11149425, 12569143, 22711857, 30078507). It has also been observed to segregate with disease in related individuals. This variant is present in population databases (rs80359187, gnomAD 0.0009%). This sequence change replaces glycine, which is neutral and non-polar, with glutamic acid, which is acidic and polar, at codon 3076 of the BRCA2 protein (p.Gly3076Glu). -

Breast-ovarian cancer, familial, susceptibility to, 1

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Institute of Human Genetics, University of Leipzig Medical Center

Aug 21, 2024

Criteria applied: PS3,PM2_SUP,PP3 -

Hereditary cancer-predisposing syndrome

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 22, 2020

The p.G3076E pathogenic mutation (also known as c.9227G>A), located in coding exon 23 of the BRCA2 gene, results from a G to A substitution at nucleotide position 9227. The glycine at codon 3076 is replaced by glutamic acid, an amino acid with similar properties.This alteration has been reported in a Japanese breast cancer patient and in a familial pancreatic and breast cancer kindred (Ikeda N et al. Int. J. Cancer. 2001 Jan;91:83-8; Hahn SA et al. J. Natl. Cancer. Inst. 2003 Feb;95:214-21). This alteration has been predicted to be pathogenic using homology-directed DNA break repair (HDR) functional assays (Guidugli L et al. Cancer Res. 2013 Jan;73:265-75; Guidugli L et al. Am. J. Hum. Genet. 2018 02;102:233-248; Hart SN et al. Genet. Med. 2019 01;21:71-80). Additionally, this alteration has been predicted to be likely deleterious using a computational method that produces a probabilistic likelihood ratio predictive of whether a missense variant impairs protein function (Karchin R et al. Cancer Inform. 2008 Apr;6:203-16). Based on our internal structural analysis, this variant is anticipated to result in a significant decrease in structural stability (Ambry internal data; Yang H et al. Science. 2002 Sep;297:1837-48). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.99

BayesDel_addAF

Pathogenic

0.50

BayesDel_noAF

Pathogenic

0.48

CADD

Pathogenic

DANN

Uncertain

1.0

Eigen

Pathogenic

0.94

Eigen_PC

Pathogenic

0.91

FATHMM_MKL

Pathogenic

0.99

M_CAP

Pathogenic

0.66

MetaRNN

Pathogenic

0.98

D;D

MetaSVM

Pathogenic

1.0

PrimateAI

Uncertain

0.67

PROVEAN

Benign

-2.1

N;N

REVEL

Pathogenic

0.92

Sift

Pathogenic

0.0

D;D

Sift4G

Pathogenic

0.0

D;D

Vest4

0.85

MutPred

0.86

Loss of sheet (P = 0.0126);Loss of sheet (P = 0.0126);

MVP

0.98

MPC

0.18

ClinPred

0.94

GERP RS

5.5

gMVP

0.87

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