chr13-32356514-G-A

Variant names:

• chr13-32356514-G-A
• rs80358978
• NM_000059.4:c.7522G>A

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
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:11 B:7 O:1
• Conservation: PhyloP100: 8.81

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]

ACMG classification

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_benign=4, Likely_pathogenic=1, Benign=2, Uncertain_significance=8, not_provided=1}. Variant chr13-32356514-G-A is described in Lovd as [Benign].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
BRCA2	NM_000059.4	c.7522G>A	p.Gly2508Ser	missense_variant	Exon 15 of 27	ENST00000380152.8	NP_000050.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
BRCA2	ENST00000380152.8	c.7522G>A	p.Gly2508Ser	missense_variant	Exon 15 of 27	5	NM_000059.4	ENSP00000369497.3
BRCA2	ENST00000530893.7	c.7153G>A	p.Gly2385Ser	missense_variant	Exon 15 of 27	1		ENSP00000499438.2
BRCA2	ENST00000614259.2	n.7522G>A		non_coding_transcript_exon_variant	Exon 14 of 26	2		ENSP00000506251.1

Frequencies

GnomAD3 genomes AF: 0.0000394 AC: 6 AN: 152222 Hom.: 0 Cov.: 31

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: 40 AN: 251392 Hom.: 0 AF XY: 0.000147 AC XY: 20 AN XY: 135868

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: 46 AN: 1461886 Hom.: 0 Cov.: 31 AF XY: 0.0000344 AC XY: 25 AN XY: 727244

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: 6 AN: 152222 Hom.: 0 Cov.: 31 AF XY: 0.0000403 AC XY: 3 AN XY: 74370

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: 13

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

Significance: Conflicting classifications of pathogenicity

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

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not specified Uncertain:2 Benign:2 Other:1

Nov 08, 2018

Genetic Services Laboratory, University of Chicago

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Dec 06, 2016

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jun 20, 2022

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.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. -

Dec 07, 2017

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Sep 19, 2013

ITMI

Significance: not provided

Review Status: no classification provided

Collection Method: reference population

- -

Hereditary cancer-predisposing syndrome Uncertain:2 Benign:1

Dec 05, 2021

Sema4, Sema4

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: curation

- -

Mar 20, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Nov 13, 2016

Color Diagnostics, LLC DBA Color Health

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Breast-ovarian cancer, familial, susceptibility to, 2 Uncertain:1 Benign:2

Feb 20, 2004

Breast Cancer Information Core (BIC) (BRCA2)

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Oct 07, 2008

Sharing Clinical Reports Project (SCRP)

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

May 28, 2019

Mendelics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Ovarian cancer Pathogenic:1 Uncertain:1

Jan 01, 2022

Laboratory of Molecular Epidemiology of Birth Defects, West China Second University Hospital, Sichuan University

Significance: Likely pathogenic

Review Status: flagged submission

Collection Method: clinical testing

- -

Jul 21, 2017

3DMed Clinical Laboratory Inc

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Breast neoplasm Uncertain:1

Nov 01, 2015

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

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: research

- -

Malignant tumor of pancreas Uncertain:1

Jul 21, 2017

3DMed Clinical Laboratory Inc

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Infiltrating duct carcinoma of breast Uncertain:1

Jul 21, 2017

3DMed Clinical Laboratory Inc

Significance: Uncertain significance

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

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) “With other allele.” 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

-

Center for Precision Medicine, Meizhou People's Hospital

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: literature only

- -

not provided Benign:1

Aug 16, 2023

Quest Diagnostics Nichols Institute San Juan Capistrano

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Hereditary breast ovarian cancer syndrome Benign:1

Jan 21, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.56
BayesDel_addAF	Uncertain	0.091	D
BayesDel_noAF	Pathogenic	0.35
CADD	Pathogenic	28
DANN	Uncertain	1.0
Eigen	Pathogenic	0.92
Eigen_PC	Pathogenic	0.88
FATHMM_MKL	Pathogenic	0.99	D
M_CAP	Uncertain	0.20	D
MetaRNN	Uncertain	0.55	D;D
MetaSVM	Uncertain	0.75	D
PrimateAI	Benign	0.42	T
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	T
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

Other links and lift over

dbSNP: rs80358978; hg19: chr13-32930651; COSMIC: COSV99061708;