rs80358443

Positions:

• chr13-32333046-A-G
• chr13-32333046-A-T

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BP4_Strong BP6

The NM_000059.4(BRCA2):​c.1568A>G​(p.His523Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000423 in 1,608,394 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). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. H523N) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.000092 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000037 (0 hom.)
• Consequence: BRCA2 NM_000059.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:15
• Conservation: PhyloP100: 0.634

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 (HGNC:):

ACMG classification

Verdict is Likely_benign. Variant got -5 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.009822488).
• BP6: Variant 13-32333046-A-G is Benign according to our data. Variant chr13-32333046-A-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 96766.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=8, Uncertain_significance=2, Benign=4}. Variant chr13-32333046-A-G is described in Lovd as [Benign]. Variant chr13-32333046-A-G is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
BRCA2	NM_000059.4	c.1568A>G	p.His523Arg	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	c.1568A>G	p.His523Arg	missense_variant	10/27	5	NM_000059.4	ENSP00000369497.3
BRCA2	ENST00000530893.7	c.1199A>G	p.His400Arg	missense_variant	10/27	1		ENSP00000499438.2
BRCA2	ENST00000614259.2	n.1568A>G		non_coding_transcript_exon_variant	9/26	2		ENSP00000506251.1

Frequencies

GnomAD3 genomes AF: 0.0000920 AC: 14 AN: 152224 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00192

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000122 AC: 30 AN: 245806 Hom.: 0 AF XY: 0.000135 AC XY: 18 AN XY: 132920

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00155

Gnomad SAS exome AF: 0.0000685

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000371 AC: 54 AN: 1456052 Hom.: 0 Cov.: 35 AF XY: 0.0000456 AC XY: 33 AN XY: 724170

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.000907

Gnomad4 SAS exome AF: 0.000118

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000180

Gnomad4 OTH exome AF: 0.0000832

GnomAD4 genome AF: 0.0000919 AC: 14 AN: 152342 Hom.: 0 Cov.: 32 AF XY: 0.0000940 AC XY: 7 AN XY: 74498

Gnomad4 AFR AF: 0.0000241

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00193

Gnomad4 SAS AF: 0.000414

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.00

Bravo AF: 0.0000718

ExAC AF: 0.000123 AC: 15

Asia WGS AF: 0.000866 AC: 3 AN: 3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2 Benign:15

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Hereditary cancer-predisposing syndrome Benign:4

Likely benign, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Nov 17, 2015	- -
Likely benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Dec 28, 2018	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	Sema4, Sema4	Jul 07, 2021	- -
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 specified Benign:3

Benign, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Apr 15, 2021	- -
Likely benign, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	Aug 15, 2023	- -
Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Sep 16, 2019	Variant summary: BRCA2 c.1568A>G (p.His523Arg) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00013 in 246858 control chromosomes, predominantly at a frequency of 0.0015 within the East Asian subpopulation in the gnomAD database. The observed variant frequency within East Asian control individuals in the gnomAD database is approximately 2 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.1568A>G has been reported in the literature predominantly among individuals of East Asian ancestry affected with Hereditary Breast and Ovarian Cancer (Cao_2016, Coulet_2010, Dong_2015, Coulet_2010, Park_2016,Seong_2009, Suter_2004, Zhong_2011, Zhong_2016, Bhaskaran_2019, Dong_2018). These report(s) do not provide unequivocal conclusions about association of the variant with Hereditary Breast and Ovarian Cancer. Co-occurrences with other pathogenic variant(s) have been reported in the literature as well as our own laboratory (BRCA2 c.2175dup, p.Val726fs (Dong_2015); BRCA1 c.5521delA, p.Ser1841fs (Dong_2018); and our laboratory, BRCA1 c.3770_3771delAG, p.Glu1257fsX9), providing supporting evidence for a benign role. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Nine 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 predominantly as likely benign/benign (Benign, n=1; Likely benign, n=6; uncertain significance, n=2). At-least one submitter has downgraded this variant from its previous classification of Likely benign to Benign. Based on the evidence outlined above, the variant was re-classified as benign. -

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

Likely benign, no assertion criteria provided	clinical testing	Sharing Clinical Reports Project (SCRP)	May 01, 2012	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Aug 07, 2015	- -

Breast neoplasm Uncertain:1 Benign:1

Likely benign, criteria provided, single submitter	clinical testing	3DMed Clinical Laboratory Inc	May 21, 2018	- -
Uncertain significance, criteria provided, single submitter	research	Laboratory of Molecular Diagnosis of Cancer, West China Hospital, Sichuan University	Nov 01, 2015	- -

Ovarian cancer Benign:1

Benign, criteria provided, single submitter

clinical testing

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

Jan 01, 2022

- -

Malignant tumor of pancreas Benign:1

Likely benign, criteria provided, single submitter

clinical testing

3DMed Clinical Laboratory Inc

May 21, 2018

- -

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

GeneDx

Feb 23, 2021

This variant is associated with the following publications: (PMID: 14973102, 22126563, 26852015, 19656164, 27124784, 28222693, 27257965, 32879886, 30415210, 30702160, 32211327, 32455662, 31825140) -

Malignant tumor of breast Benign:1

Likely benign, no assertion criteria provided

clinical testing

Department of Pathology and Laboratory Medicine, Sinai Health System

-

The BRCA2 p.His523Arg variant was identified in 4 of 2740 proband chromosomes (frequency: 0.001) from Chinese and Korean individuals or families with breast cancer, benign breast disease and ESCC (esophageal squamous cell cancer), and was identified in 2 of 1168 control chromosomes (frequency: 0.002) from healthy individuals (Cao 2016, Seong M-W 2009, Suter 2004, Zhong 2011). The variant was (also) identified by our laboratory in 1 Chinese individual with breast cancer. The variant was also identified in dbSNP (ID: rs80358443) “With Likely benign/Uncertain significance allele”, Clinvitae database (classification likely benign), the ClinVar database (classification likely benign, submitters: Ambry Genetics, GeneDx, SCRP (Sharing Clinical Reports Project), derived from Myriad reports), GeneInsight COGR database (unclassified “by a clinical laboratory”), and UMD (2X as an ”unclassified variant”). It was identified in the Exome Aggregation Consortium (ExAC) database (released Jan 13, 2015) in 13 of 8636 chromosomes (frequency: 0.0015) from a population of East Asians, and in 2 of 16334 (frequency: 0.0001) in a South Asian population. In EXAC, it was not seen in the European (Non-Finnish), Other, African, Latino and European (Finnish) populations, increasing the likelihood that this may be a low frequency benign variant in certain populations of origin. The p.His523 residue is not conserved in mammals, (with Ser, Cys and Asn present) and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to the protein; however, this information is not predictive enough to rule out pathogenicity. The variant occurs outside of the splicing consensus sequence and 2 of 5 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) predict a greater than 10% difference in splicing; this is not very predictive of pathogenicity. In summary, based on the above information, the clinical significance of this variant cannot be determined with certainty at this time although we would lean towards a more benign role for this variant. This variant is classified as likely benign. -

Familial cancer of breast Benign:1

Likely benign, no assertion criteria provided

literature only

Center for Precision Medicine, Meizhou People's Hospital

-

- -

Hereditary breast ovarian cancer syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 21, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.072
BayesDel_addAF	Benign	-0.40	T
BayesDel_noAF	Benign	-0.34
CADD	Benign	6.5
DANN	Benign	0.28
Eigen	Benign	-1.4
Eigen_PC	Benign	-1.4
FATHMM_MKL	Benign	0.0062	N
M_CAP	Benign	0.061	D
MetaRNN	Benign	0.0098	T;T
MetaSVM	Benign	-0.92	T
PrimateAI	Benign	0.26	T
PROVEAN	Benign	-0.58	N;N
REVEL	Uncertain	0.32
Sift	Benign	0.048	D;D
Sift4G	Benign	0.11	T;T
Vest4		0.14
MutPred		0.10		Gain of phosphorylation at S521 (P = 0.0935);Gain of phosphorylation at S521 (P = 0.0935);
MVP		0.77
MPC		0.028
ClinPred		0.017	T
GERP RS		-1.7
gMVP		0.057

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: rs80358443; hg19: chr13-32907183; COSMIC: COSV101204659;