rs80359036

Positions:

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BP4_StrongBP6

The NM_000059.4(BRCA2):c.800G>A(p.Gly267Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000162 in 1,601,114 control chromosomes in the GnomAD database, with no homozygous occurrence. 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: 𝑓 0.000020 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000016 ( 0 hom. )

Consequence

BRCA2
NM_000059.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:7B:6

Conservation

PhyloP100: 0.991

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 Likely_benign. Variant got -5 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.06330904).

BP6

Variant 13-32332278-G-A is Benign according to our data. Variant chr13-32332278-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 52472.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=6, Uncertain_significance=5}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
BRCA2	NM_000059.4 linkuse as main transcript	c.800G>A	p.Gly267Glu	missense_variant	10/27	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.800G>A	p.Gly267Glu	missense_variant	10/27	5	NM_000059.4	ENSP00000369497	A2

Frequencies

GnomAD3 genomes

AF:

0.0000197

AC:

AN:

152078

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000294

Gnomad OTH

AF:

0.000478

GnomAD3 exomes

AF:

0.0000246

AC:

AN:

243540

Hom.:

AF XY:

0.0000152

AC XY:

AN XY:

131888

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:

0.0000538

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000159

AC:

AN:

1449036

Hom.:

Cov.:

AF XY:

0.0000125

AC XY:

AN XY:

720786

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000465

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000119

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000118

Gnomad4 OTH exome

AF:

0.0000334

GnomAD4 genome

AF:

0.0000197

AC:

AN:

152078

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74302

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000294

Gnomad4 OTH

AF:

0.000478

Alfa

AF:

0.0000193

Hom.:

Bravo

AF:

0.0000189

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000117

AC:

ExAC

AF:

0.0000330

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:7Benign:6

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Hereditary cancer-predisposing syndrome

Uncertain:1Benign:3

Uncertain significance, criteria provided, single submitter	curation	Sema4, Sema4	Nov 22, 2021	- -
Likely benign, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Jan 08, 2016	- -
Likely benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Jan 25, 2019	This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -
Likely benign, criteria provided, single submitter	curation	University of Washington Department of Laboratory Medicine, University of Washington	Mar 23, 2023	Missense variant in a coldspot region where missense variants are very unlikely to be pathogenic (PMID:31911673). -

not provided

Uncertain:2Benign:1

Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Apr 29, 2021	In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 24121792, 25348012, 27882536, 26740942, 29297111, 28288110, 30212499, 31294896, 31131967, 32438681, 31112341, 30040829) -
Uncertain significance, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Mar 19, 2020	- -
Uncertain significance, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Jun 10, 2020	The BRCA2 c.800G>A; p.Gly267Glu variant (rs80359036) is reported in the literature in several individuals affected with breast and/or ovarian cancer, although its clinical significance in these individuals was not determined (Alhuqail 2018, Davies 2017, Loizidou 2017, Santonocito 2020). This variant is found on only six chromosomes (6/111498 alleles) in the Genome Aggregation Database. The glycine at codon 267 is weakly conserved, and computational analyses (SIFT, PolyPhen-2) predict that this variant is tolerated. Functional studies suggest normal DNA damage repair activity, but cells expressing this variant exhibit defects in cytokinesis (von Nicolai 2016). Due to limited information, the clinical significance of the Gly267Glu variant is uncertain at this time. References: Alhuqail AJ et al. High prevalence of deleterious BRCA1 and BRCA2 germline mutations in arab breast and ovarian cancer patients. Breast Cancer Res Treat. 2018;168(3):695-702. Davies H et al. HRDetect is a predictor of BRCA1 and BRCA2 deficiency based on mutational signatures. Nat Med. 2017;23(4):517-525. Loizidou MA et al. BRCA1 and BRCA2 mutation testing in Cyprus; a population based study. Clin Genet. 2017;91(4):611-615. Santonocito C et al. Spectrum of Germline BRCA1 and BRCA2 Variants Identified in 2351 Ovarian and Breast Cancer Patients Referring to a Reference Cancer Hospital of Rome. Cancers (Basel). 2020;12(5):E1286. von Nicolai C. Characterization of a novel DNA binding domain in the N-terminus of BRCA2 and evaluation of BRCA2 variants identified in breast cancer patients in the same region. Biomolecules (q-bio.BM). Universite Paris-Saclay, 2016. English. NNT:2016SACLS123. -

Breast-ovarian cancer, familial, susceptibility to, 2

Uncertain:2

Uncertain significance, no assertion criteria provided	clinical testing	Breast Cancer Information Core (BIC) (BRCA2)	May 29, 2002	- -
Uncertain significance, no assertion criteria provided	clinical testing	Department of Pathology and Laboratory Medicine, Sinai Health System	-	The BRCA2 p.Gly267Glu variant was identified in 1 of 1120 proband chromosomes (frequency: 0.0009) from individuals with breast cancer and was classified as uncertain significance (Davies 2017 PMID: 28288110). The variant was also identified in dbSNP (ID: rs80359036) as "With Uncertain significance allele", in ClinVar (Likely Benign 1x by Ambry, Uncertain Significance 5x by CHEO, GeneDx, Quest, Invitae and BIC), Cosmic (2x classified as neutral), and UMD-LSDB (15x classified as unknown variant and in one case identified with co-occurring pathogenic variant BRCA2 c.7235insG). The variant was not identified in GeneInsight-COGR, MutDB, LOVD 3.0, BIC Database, ARUP Laboratories, or Zhejiang Colon Cancer Database. The variant was identified in control databases in 7 of 239416 chromosomes at a frequency of 0.00003 (Genome Aggregation Database Feb 27, 2017). Breakdown of the observations by population include European Non-Finnish in 7 of 109718 chromosomes (freq: 0.00006), while the variant was not observed in the African, Other, Latino, Ashkenazi Jewish, East Asian, Finnish, and South Asian populations. Although the p.Gly267Glu residue is not conserved in mammals and other organisms, 4 of 5 computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) suggest that the G variant may impact the protein. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) do not predict a difference in splicing. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance. -

not specified

Uncertain:1Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Oct 16, 2023	Variant summary: BRCA2 c.800G>A (p.Gly267Glu) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. TA recent report from the CAGI5 (fifth Critical Assessment of Genome Interpretation) challenge has classified this variant as a VUS (class 3: 0.05<p<0.949) in a prediction protocol that includes assessment of the impact of this variant on splicing and protein function using four sets of predictors (Padilla_2019). The variant allele was found at a frequency of 2.5e-05 in 243540 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. The variant, c.800G>A, has been listed to be found in an individual affected with Fanconi anemia, however no further details were provided on this case (Nicchia_2015), in addition, the variant was also reported as a VUS in settings of multigene panel testing among individuals affected with breast/ovarian cancer (e.g. Davies_2018, Loizidou_2017, Joharah Alhuqail_2018, Kowalik_2018, Machakova_2019, Santonocito_2020, Abdel-Rezeq_2022, Bhai_2021), however it was also found in controls (e.g. it was found in 1/7325 European American women, who are older than age 70 years, and who have never had cancer in the FLOSSIES database). These reports do not provide unequivocal conclusions about association of the variant with Hereditary Breast and Ovarian Cancer Syndrome. In a recent large study evaluating breast cancer cases and controls in the Breast Cancer Association Consortium (BCAC), the variant was reported in 4/60466 cases, but was also found in 5/53461 controls (Dorling_2021, reported through LOVD). In addition, at-least one co-occurrence with another pathogenic variant has been reported in the UMD database (BRCA2 c.7235insG, p.Thr2412SerfsX2), providing supporting evidence for a benign role. To our knowledge, no peer-reviewed publications report experimental evidence evaluating an impact on protein function. The following publications have been ascertained in the context of this evaluation (PMID: 35402282, 34326862, 31294896, 28288110, 33471991, 24121792, 29297111, 30040829, 27882536, 31409081, 25348012, 26740942, 31112341, 31131967, 32438681, vonNicolai_no PMID). Eight submitters have cited clinical-significance assessments for this variant to ClinVar after 2014 (VUS, n=3, Likely benign, n=5). Based on the evidence outlined above, the variant was classified as VUS-possibly benign. -
Likely benign, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	Feb 06, 2024	- -

Breast and/or ovarian cancer

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario

Aug 16, 2022

- -

Hereditary breast ovarian cancer syndrome

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 24, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.11

BayesDel_addAF

Benign

-0.29

BayesDel_noAF

Benign

-0.47

CADD

Benign

0.56

DANN

Benign

0.30

Eigen

Benign

-1.4

Eigen_PC

Benign

-1.4

FATHMM_MKL

Benign

0.0076

M_CAP

Benign

0.037

MetaRNN

Benign

0.063

T;T

MetaSVM

Benign

-0.93

MutationTaster

Benign

1.0

N;N

PrimateAI

Benign

0.22

PROVEAN

Benign

-0.80

N;N

REVEL

Uncertain

0.33

Sift

Benign

0.90

T;T

Sift4G

Benign

1.0

T;T

Vest4

0.16

MVP

0.70

MPC

0.026

ClinPred

0.030

GERP RS

-2.5

gMVP

0.075

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