rs80358566

Positions:

• chr13-32337573-A-G
• chr13-32337573-A-T

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 0P and 3B. BP4_Moderate BP6

The NM_000059.4(BRCA2):​c.3218A>G​(p.Gln1073Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000668 in 1,601,338 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. Q1073H) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.000079 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000066 (0 hom.)
• Consequence: BRCA2 NM_000059.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:5 B:10
• Conservation: PhyloP100: 1.48

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 -3 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.24077302).
• BP6: Variant 13-32337573-A-G is Benign according to our data. Variant chr13-32337573-A-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 37828.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=3, Likely_benign=8}. Variant chr13-32337573-A-G is described in Lovd as [Likely_benign].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
BRCA2	NM_000059.4	c.3218A>G	p.Gln1073Arg	missense_variant	11/27	ENST00000380152.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
BRCA2	ENST00000380152.8	c.3218A>G	p.Gln1073Arg	missense_variant	11/27	5	NM_000059.4	A2

Frequencies

GnomAD3 genomes AF: 0.0000788 AC: 12 AN: 152238 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: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000176

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000659 AC: 16 AN: 242708 Hom.: 0 AF XY: 0.0000686 AC XY: 9 AN XY: 131184

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: 0.000135

Gnomad OTH exome AF: 0.000170

GnomAD4 exome AF: 0.0000656 AC: 95 AN: 1449100 Hom.: 0 Cov.: 32 AF XY: 0.0000667 AC XY: 48 AN XY: 719358

Gnomad4 AFR exome AF: 0.0000305

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000832

Gnomad4 OTH exome AF: 0.0000334

GnomAD4 genome AF: 0.0000788 AC: 12 AN: 152238 Hom.: 0 Cov.: 32 AF XY: 0.0000807 AC XY: 6 AN XY: 74386

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: 0.000176

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000762 Hom.: 0

Bravo AF: 0.0000642

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.00 AC: 0

ExAC AF: 0.0000494 AC: 6

EpiCase AF: 0.000109

EpiControl AF: 0.000237

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:5 Benign:10

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Breast-ovarian cancer, familial, susceptibility to, 2 Uncertain:3 Benign:1

Likely benign, no assertion criteria provided	clinical testing	Sharing Clinical Reports Project (SCRP)	Mar 18, 2013	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Counsyl	Feb 19, 2016	- -
Uncertain significance, no assertion criteria provided	clinical testing	Breast Cancer Information Core (BIC) (BRCA2)	Feb 20, 2004	- -
Uncertain significance, no assertion criteria provided	clinical testing	Zotz-Klimas Genetics Lab, MVZ Zotz Klimas	Oct 30, 2023	- -

Hereditary cancer-predisposing syndrome Benign:3

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). -
Likely benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Nov 14, 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	clinical testing	Color Diagnostics, LLC DBA Color Health	Feb 22, 2016	- -

not specified Uncertain:1 Benign:1

Likely benign, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	Jul 31, 2024	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Oct 13, 2023	Variant summary: BRCA2 c.3218A>G (p.Gln1073Arg) results in a conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 6.6e-05 in 242708 control chromosomes, predominantly at a frequency of 0.00014 within the Non-Finnish European subpopulation in the gnomAD database. This frequency is not significantly higher than estimated for a pathogenic variant in BRCA2 causing Hereditary Breast And Ovarian Cancer Syndrome (6.6e-05 vs 0.00075), allowing no conclusion about variant significance. c.3218A>G has been reported in the literature in individuals affected with breast and/or ovarian cancer, prostate cancer, urothelial cancer and uterine cancer (Zhu_2020, Alsop_2012, Lu_2012, Maier_2014, Rodriguez-Vida_2014, Lu_2015), without strong evidence for causality. In addition, this variant has been reported insignificantly present in both case and control cohorts in a large case-control study of breast cancer (4/60466 cases vs 3/53461 controls, Dorling_2021). Functional studies show that this variant alters the BRCA2-APRIN interaction independently of the BRC1-RAD51 interaction but was able to partially rescue homologous recombination in BRCA2-deficient cells to about 65% of normal function (Brough_2012). Eight submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. Multiple submitters reported the variant with conflicting assessments (VUS, n=3, Likely benign, n=5). Based on the evidence outlined above, the variant was classified as VUS-possibly benign. -

not provided Uncertain:1 Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	May 04, 2021	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	May 20, 2019	This variant is associated with the following publications: (PMID: 28726806, 27067391, 26497743, 22293751, 22711857, 25111659) -

Hereditary breast ovarian cancer syndrome Benign:2

Likely benign, criteria provided, single submitter	curation	German Consortium for Hereditary Breast and Ovarian Cancer, University Hospital Cologne	Jan 08, 2024	. According to the ClinGen ENIGMA BRCA2 v1.0.0 criteria we chose this criterium: BP1 (strong benign): BP1_Strong for silent substitution, missense or in-frame insertion, deletion or delins variants outside a (potentially) clinically important functional domain AND no splicing predicted (spliceAI: BRCA2: 0.0) -
Likely benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -

Breast and/or ovarian cancer Benign:1

Likely benign, criteria provided, single submitter

clinical testing

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

Jan 25, 2023

- -

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.Gln1073Arg variant was identified in dbSNP (ID: rs80358566) as “other”, Clinvitae database (classified as likely benign by ClinVar; uncertain significance by ClinVar and Invitae), the ClinVar database (classified as likely benign by SCRP, GeneDx; uncertain significance by Invitae, Ambry Genetics, BIC), the BIC database (3x with unknown clinical importance). This variant was also identified in the Exome Aggregation Consortium database (August 8th 2016) in 6 of 119496 chromosomes (freq. 0.00005) in the European population in 6 of 65970 chromosomes (freq.0.0001), but was not seen in African, Asian, Finnish, Latino and Other populations. The variant was not identified in the Fanconi Anemia Mutation Database (LOVD), ARUP Laboratories BRCA Mutations Database, COSMIC and GeneInsight-COGR databases. The p.Gln1073 residue is not conserved in mammals and four out of five 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 3 of 5 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) predict the loss of a cryptic 3’ splice site. However, this information is not predictive enough to assume pathogenicity. In addition, the variant was identified, in a sample used as a positive control, as co-occurring with a pathogenic variant in BRCA1 (c.5136G>A, p.Trp1712X), increasing the likelihood this variant does not have clinical significance (Mucaki 2016). 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.26	T
BayesDel_noAF	Benign	-0.37
CADD	Benign	11
DANN	Benign	0.92
Eigen	Benign	-0.56
Eigen_PC	Benign	-0.70
FATHMM_MKL	Benign	0.20	N
M_CAP	Benign	0.084	D
MetaRNN	Benign	0.24	T;T
MetaSVM	Benign	-0.91	T
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.29	T
PROVEAN	Uncertain	-3.4	D;D
REVEL	Benign	0.17
Sift	Uncertain	0.029	D;D
Sift4G	Benign	0.41	T;T
Vest4		0.29
MVP		0.86
MPC		0.13
ClinPred		0.26	T
GERP RS		1.4
gMVP		0.34

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: rs80358566; hg19: chr13-32911710; COSMIC: COSV105932267; COSMIC: COSV105932267;