rs80358978

Positions:

Variant summary

Our verdict is Likely benign. Variant got -1 ACMG points: 0P and 1B. BP6

The NM_000059.4(BRCA2):c.7522G>A(p.Gly2508Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000322 in 1,614,108 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.000039 ( 0 hom., cov: 31)

Exomes 𝑓: 0.000031 ( 0 hom. )

Consequence

BRCA2
NM_000059.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1U:11B:7O:1

Conservation

PhyloP100: 8.81

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 -1 ACMG points.

BP6

Variant 13-32356514-G-A is Benign according to our data. Variant chr13-32356514-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 52347.We mark this variant Likely_benign, oryginal submissions are: {Likely_pathogenic=1, Benign=2, Uncertain_significance=8, Likely_benign=4, not_provided=1}. Variant chr13-32356514-G-A is described in Lovd as [Benign].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
BRCA2	NM_000059.4 linkuse as main transcript	c.7522G>A	p.Gly2508Ser	missense_variant	15/27	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.7522G>A	p.Gly2508Ser	missense_variant	15/27	5	NM_000059.4	ENSP00000369497	A2

Frequencies

GnomAD3 genomes

AF:

0.0000394

AC:

AN:

152222

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:

0.00115

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000159

AC:

AN:

251392

Hom.:

AF XY:

0.000147

AC XY:

AN XY:

135868

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00217

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000315

AC:

AN:

1461886

Hom.:

Cov.:

AF XY:

0.0000344

AC XY:

AN XY:

727244

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00111

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.0000331

GnomAD4 genome

AF:

0.0000394

AC:

AN:

152222

Hom.:

Cov.:

AF XY:

0.0000403

AC XY:

AN XY:

74370

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00115

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000453

ExAC

AF:

0.000107

AC:

Asia WGS

AF:

0.000289

AC:

AN:

3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1Uncertain:11Benign:7Other:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not specified

Uncertain:2Benign:2Other:1

Uncertain significance, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Nov 08, 2018	- -
Likely benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jun 20, 2022	Variant summary: BRCA2 c.7522G>A (p.Gly2508Ser) results in a non-conservative amino acid change located in the helical domain (IPR015252) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.0002 in 310330 control chromosomes, predominantly at a frequency of 0.0023 within the East Asian subpopulation in the gnomAD database. The observed variant frequency within East Asian control individuals in the gnomAD database is approximately 3-fold of the estimated maximal expected allele frequency for a pathogenic variant in BRCA2 causing Hereditary Breast and Ovarian Cancer Syndrome (HBOC) phenotype (0.00075), strongly suggesting that the variant is a benign polymorphism found primarily in populations of East Asian origin. The variant, c.7522G>A, has been reported in the literature in numerous individuals affected with tumors that belong to the HBOC spectrum, however it was also found in several healthy controls. These reports do not provide unequivocal conclusions about association of the variant with Hereditary Breast and Ovarian Cancer Syndrome. Co-occurrences with other pathogenic variants have been reported (BRCA2 c.8340_8343delTAAC (p.Asn2781ValfsX39) in the BIC database and BRCA1 c.3627dupA (p.Glu1210Argfs) in Lim_2009), providing supporting evidence for a benign role. A large case-control study involving breast cancer patients and controls of Asian ancestry (Han_2017), found an enrichment of this variant in cases (OR: 3.02 (95%CI: 1.69-5.39), p-value: 0.000123). However, an other case-control association study, involving breast cancer patients and controls of Japanese ancestry (Momozawa_2018), did not demonstrate significant increase in breast/ovarian cancer risk (i.e. the variant was identified in 5/7051 female cases, and 6/11241 female controls; OR: 1.3 (95%CI: 0.3-5.2)). A further study, involving Korean breast cancer patients, where multifactorial probability was estimated by performing systematic assessments of variants of unknown significance in the BRCA genes (which included analysis of co-occurrence with known deleterious mutations, personal and family history of cancer and tumor pathology), predicted this variant to be likely pathogenic, although the variant was interpreted as likely benign when applying the ACMG/AMP guidelines (Lee_2018). Several publications reported experimental evidence evaluating an impact on protein function, and demonstrated a mild impact on BRCA2 function, representing an activity comparable to wild-type, or a somewhat hypomorphic allele (e.g. Shimelis_2017, Mesman_2018, Guidugli_2018, Ikegami_2020). Eleven other clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Multiple laboratories reported the variant with conflicting assessments (VUS, n=6, likely benign, n=3 or benign, n=2). Based on the evidence outlined above, the variant was classified as likely benign. -
not provided, no classification provided	reference population	ITMI	Sep 19, 2013	- -
Uncertain significance, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Dec 06, 2016	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Dec 07, 2017	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Hereditary cancer-predisposing syndrome

Uncertain:2Benign:1

Likely benign, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Nov 13, 2016	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Ambry Genetics	Mar 20, 2024	The p.G2508S variant (also known as c.7522G>A), located in coding exon 14 of the BRCA2 gene, results from a G to A substitution at nucleotide position 7522. The glycine at codon 2508 is replaced by serine, an amino acid with similar properties. This alteration has been detected in multiple individuals diagnosed with breast and/or ovarian cancer (Suter NM et al. Cancer Epidemiol. Biomarkers Prev. 2004 Feb;13:181-9; Lim MC et al. J. Cancer Res. Clin. Oncol. 2009 Nov;135:1593-9; Ng PS et al. Clin. Genet. 2016 Oct;90:315-23; Yoon KA et al. Cancer Res Treat. 2017 Jul;49:627-634; Liang Y et al. Med. Sci. Monit. 2018 Apr;24:2465-2475; Wen WX et al. J. Med. Genet. 2018 Feb;55:97-103; Li JY et al. Int. J. Cancer. 2019 Jan;144:281-289; Zhang Y et al. BMC Cancer, 2022 Aug;22:842). Multiple case-control studies and a meta-analysis of the participants from the Breast Cancer Association Consortium and the Shanghai Breast Cancer Genetic Study show a statistically increased association of this variant with breast cancer (Zhang Y et al. Cancer Epidemiol. Biomarkers Prev. 2014 Apr;23:622-8; Han MR et al. Carcinogenesis. 2017 May;38:511-518; Shimelis H et al. Cancer Res. 2017 Jun;77:2789-2799). Various functional assays indicate that this alteration is intermediately impaired with respect to rescue of lethality in Brca2-null mouse embryonic stem cells, homology directed repair in two cell lines, and PARP inhibition (Shimelis H et al. Cancer Res. 2017 Jun;77:2789-2799). This alteration has been seen with two different pathogenic mutations and one likely pathogenic variant in BRCA2 (phase unknown) in individuals whose clinical histories are not suggestive of Fanconi Anemia (Ambry internal data). Based on data from gnomAD, the frequency for this variant is above the maximum credible frequency for a disease-causing variant in this gene based on internally established thresholds (Karczewski et al. Nature. 2020 May;581(7809):434-443; Whiffin et al. Genet Med. 2017 10;19:1151-1158). 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 available evidence, the clinical significance of this alteration remains unclear. -
Uncertain significance, criteria provided, single submitter	curation	Sema4, Sema4	Dec 05, 2021	- -

Breast-ovarian cancer, familial, susceptibility to, 2

Uncertain:1Benign:2

Uncertain significance, no assertion criteria provided	clinical testing	Breast Cancer Information Core (BIC) (BRCA2)	Feb 20, 2004	- -
Likely benign, no assertion criteria provided	clinical testing	Sharing Clinical Reports Project (SCRP)	Oct 07, 2008	- -
Benign, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -

Ovarian cancer

Pathogenic:1Uncertain:1

Likely pathogenic, flagged submission	clinical testing	Laboratory of Molecular Epidemiology of Birth Defects, West China Second University Hospital, Sichuan University	Jan 01, 2022	- -
Uncertain significance, criteria provided, single submitter	clinical testing	3DMed Clinical Laboratory Inc	Jul 21, 2017	- -

Malignant tumor of pancreas

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

3DMed Clinical Laboratory Inc

Jul 21, 2017

- -

Breast neoplasm

Uncertain:1

Uncertain significance, criteria provided, single submitter

research

Laboratory of Molecular Diagnosis of Cancer, West China Hospital, Sichuan University

Nov 01, 2015

- -

Infiltrating duct carcinoma of breast

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

3DMed Clinical Laboratory Inc

Jul 21, 2017

- -

Malignant tumor of breast

Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

Department of Pathology and Laboratory Medicine, Sinai Health System

The BRCA2, p.Gly2508Ser variant was identified in 6 of 1220 proband chromosomes (frequency: 0.005) from individuals or families with breast, ovarian and thyroid cancers. (Lim 2009, Yu 2015, Wong 2016). The variant was also identified 1x in a study of 681 health controls in an east Asian individual (Bodian 2014). The variant was also identified in dbSNP (ID: rs80358978) â€šÃ„ÃºWith other allele.â€šÃ„Ã¹ This variant was identified in the Exome Aggregation Consortium (ExAC) database (March 14, 2016) in 13 of 8636 chromosomes (frequency: 0 0.0015) in the East Asian population, and was not found in populations of South Asians, European (Non-Finnish), African, Latino, European (Finnish) and other individuals, increasing the likelihood that this may be a low frequency benign variant in certain populations of origin. In the Clinvar Database the variant was identified with conflicting interpretations: as likely benign by Invitae, GeneDX and Sharing Reports Project derived from Myriad reports, as uncertain significance by Ambry Genetics and BIC,classification was not provided by ITMI. In BIC the variant was identified 4x with unknown clinical significance. In the Fanconi Anaemia Mutation Database (LOVD) the variant was identified 2x (1x as neutral by Karchin 2008 and 1x as deleterious by Pettigrew 2008). This variant was not identified in NHLBI Exome Sequencing Project (Exome Variant Server), COSMIC, GeneInsight COGR, or ARUP Laboratories Databases. The p.Gly2508 residue is conserved across mammals and lower organisms, and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) suggest that the Ser (Serine) variant may impact the protein. However, this information is not predictive enough to assume pathogenicity. Karchin et al 2008 has concluded the variant as predicted neutral using protein likelihood ratios to determine all variants of undetermined significance in the C-terminal binding domain of the BRCA2 protein. However, the variant was predicted to result in an increased exonic splice enhancer (ESE) motif score at an evolutionarily conserved ESE (Pettigrew 2008) and therefore the variant was concluded to be deleterious. In a multigene panel study of breast cancer predisposition in Asians, the authors categorized the p.Gly2508Ser variant as pathogenic using Manchester and Boadicea scores. Family history was evaluated in this multigene study (Wong 2016). 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. -

Familial cancer of breast

Uncertain:1

Uncertain significance, no assertion criteria provided

literature only

Center for Precision Medicine, Meizhou People's Hospital

- -

not provided

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Quest Diagnostics Nichols Institute San Juan Capistrano

Aug 16, 2023

- -

Hereditary breast ovarian cancer syndrome

Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Feb 01, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.56

BayesDel_addAF

Uncertain

0.091

BayesDel_noAF

Pathogenic

0.35

CADD

Pathogenic

DANN

Uncertain

1.0

Eigen

Pathogenic

0.92

Eigen_PC

Pathogenic

0.88

FATHMM_MKL

Pathogenic

0.99

M_CAP

Uncertain

0.20

MetaRNN

Uncertain

0.55

D;D

MetaSVM

Uncertain

0.75

MutationTaster

Benign

1.0

D;D

PrimateAI

Benign

0.42

PROVEAN

Benign

-1.8

N;N

REVEL

Pathogenic

0.78

Sift

Pathogenic

0.0

D;D

Sift4G

Pathogenic

0.0

D;D

Vest4

0.86

MutPred

0.81

Gain of disorder (P = 0.0388);Gain of disorder (P = 0.0388);

MVP

0.97

MPC

0.17

ClinPred

0.35

GERP RS

5.5

gMVP

0.62

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.11

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