rs55986646

chr13-32333122-G-Achr13-32333122-G-C

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_Strong BP6_Very_Strong BP7

The NM_000059.4(BRCA2):c.1644G>A(p.Gln548=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000502 in 1,614,046 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★★).

• Frequency:
  • Genomes: 𝑓 0.000072 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000048 (0 hom.)
• Consequence: BRCA2 NM_000059.4 synonymous
• Clinical Significance: Benign reviewed by expert panel B:11
• Conservation: PhyloP100: 0.426

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 Benign. Variant got -13 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.66).
• BP6: Variant 13-32333122-G-A is Benign according to our data. Variant chr13-32333122-G-A is described in ClinVar as [Benign]. Clinvar id is 51164.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr13-32333122-G-A is described in Lovd as [Likely_benign]. Variant chr13-32333122-G-A is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=0.426 with no splicing effect.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
BRCA2	NM_000059.4	c.1644G>A	p.Gln548=	synonymous_variant	10/27	ENST00000380152.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
BRCA2	ENST00000380152.8	c.1644G>A	p.Gln548=	synonymous_variant	10/27	5	NM_000059.4	A2

Frequencies

GnomAD3 genomes AF: 0.0000723 AC: 11 AN: 152204 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00211

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: 0.000247 AC: 62 AN: 251082 Hom.: 0 AF XY: 0.000221 AC XY: 30 AN XY: 135714

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00337

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: 0.0000479 AC: 70 AN: 1461724 Hom.: 0 Cov.: 35 AF XY: 0.0000440 AC XY: 32 AN XY: 727152

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00164

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 8.99e-7

Gnomad4 OTH exome AF: 0.0000662

GnomAD4 genome AF: 0.0000722 AC: 11 AN: 152322 Hom.: 0 Cov.: 32 AF XY: 0.0000940 AC XY: 7 AN XY: 74486

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00212

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

Bravo AF: 0.000102

ClinVar

Significance: Benign

Submissions summary: Benign:11

Revision: reviewed by expert panel

Submissions by phenotype

Breast-ovarian cancer, familial, susceptibility to, 2 Benign:4

Benign, no assertion criteria provided	clinical testing	Breast Cancer Information Core (BIC) (BRCA2)	Sep 18, 2010	- -
Benign, criteria provided, single submitter	clinical testing	All of Us Research Program, National Institutes of Health	Dec 13, 2023	- -
Benign, no assertion criteria provided	clinical testing	Department of Pathology and Laboratory Medicine, Sinai Health System	-	The BRCA2 p.Gln548Gln variant was identified in the literature in one Chinese family with hereditary breast and ovarian cancer (Thirthagiri 2008); however, control chromosomes from healthy individuals were not evaluated in this study. The variant was also identified in dbSNP (ID: rs rs55986646) “With likely benign allele”, in the 1000 Genomes Project, in 1 of 5000 chromosomes (frequency 0.0002). It was also identified in the Exome Aggregation Consortium (ExAC) database (January 13, 2015) in 28 of 121014 chromosomes (frequency: 0.0002) (or 28 individuals from a population of 8644 East Asian individuals (frequency: 0.003)), and not from European (Non-Finnish)/African/Latino/South Asian/European (Finnish) or other individuals; the Clinvitae database classified the variant as benign/likely benign; ClinVar (4X, classified as a benign by BIC and GeneDX; likely benign by Ambry Genetics), and UMD (2X as a 3-unclassified variant variant, co-occurring with a pathogenic BRCA2 variant (c.1212delT (p.Asn404LysfsX26), increasing the likelihood that the p.Gln548Gln variant does not have clinical significance). The variant was also identified by our laboratory in 3 individuals with breast, and ovarian cancer including one with a co-occurring pathogenic variant (BRCA2 c.246delA), increasing the likelihood the p.Gln548Gln variant does not have clinical significance. The p.Gln548Gln variant is not expected to have clinical significance because it does not result in a change of amino acid and is not located in a known consensus splice site. However, four out of five in-silico splicing tools predict abolishment of a 3’ splice site in a region not expected to be involved in splicing, but this information is not very predictive of pathogenicity. In summary, based on the above information, this variant meets our laboratories criteria to be classified as benign. -
Benign, reviewed by expert panel	curation	Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA)	Jun 29, 2017	Synonymous substitution variant, with low bioinformatic likelihood to alter mRNA splicing (splicing prior 0.02; http://priors.hci.utah.edu/PRIORS/) and frequency 0.0032 (East Asian), derived from ExAC (2014-12-17). -

Hereditary cancer-predisposing syndrome Benign:3

Likely benign, criteria provided, single submitter	curation	Sema4, Sema4	Jan 14, 2022	- -
Benign, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Nov 30, 2015	- -
Likely benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Dec 10, 2014	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. -

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	May 02, 2019	Variant summary: BRCA2 c.1644G>A alters a non-conserved nucleotide resulting in a synonymous change. 5/5 computational tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 0.00024 in 274202 control chromosomes, predominantly at a frequency of 0.0034 within the East Asian subpopulation in the gnomAD database. The observed variant frequency within East Asian control individuals in the gnomAD database is approximately 5 fold of the estimated maximal expected allele frequency for a pathogenic variant in BRCA2 causing Hereditary Breast and Ovarian Cancer phenotype (0.00075), strongly suggesting that the variant is a benign polymorphism found primarily in populations of East Asian origin. c.1644G>A has been reported in the literature in individuals with personal and/or family history of Hereditary Breast and Ovarian Cancer (Hwang_2017, Trujillano_2015, Thirthagiri_2008, Suter_2004). These reports do not provide unequivocal conclusions about association of the variant with Hereditary Breast and Ovarian Cancer. Co-occurrences with a pathogenic variant have been reported (BRCA2 c.1212delT, p.Asn404Lysfs*26; UMD), providing supporting evidence for a benign role. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Four ClinVar submitters including an expert panel (ENIGMA) (evaluation after 2014) cite the variant as benign. Based on the evidence outlined above, the variant was classified as benign. -
Benign, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	Aug 15, 2023	- -

BRCA2-related disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Jul 02, 2019

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). -

Hereditary breast ovarian cancer syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 25, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.66
Cadd	Benign	1.1
Dann	Benign	0.47

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

Other links and lift over

dbSNP: rs55986646; hg19: chr13-32907259; COSMIC: COSV66452122;