rs80359174

Variant names:

• chr13-32380064-A-G
• rs80359174
• NM_000059.4:c.9175A>G

Your query was ambiguous. Multiple possible variants found:

• chr13-32380064-A-G
• chr13-32380064-A-T

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP4_Moderate BP6_Very_Strong

The NM_000059.4(BRCA2):​c.9175A>G​(p.Lys3059Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000629 in 1,461,780 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 11/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.000063 (0 hom.)
• Consequence: BRCA2 NM_000059.4 missense
• Clinical Significance: Benign reviewed by expert panel U:4 B:7
• Conservation: PhyloP100: 0.900

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 -10 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.1261653).
• BP6: Variant 13-32380064-A-G is Benign according to our data. Variant chr13-32380064-A-G is described in ClinVar as [Benign]. Clinvar id is 52767.Status of the report is reviewed_by_expert_panel, 3 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
BRCA2	NM_000059.4	c.9175A>G	p.Lys3059Glu	missense_variant	Exon 24 of 27	ENST00000380152.8	NP_000050.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
BRCA2	ENST00000380152.8	c.9175A>G	p.Lys3059Glu	missense_variant	Exon 24 of 27	5	NM_000059.4	ENSP00000369497.3
BRCA2	ENST00000530893.7	c.8806A>G	p.Lys2936Glu	missense_variant	Exon 24 of 27	1		ENSP00000499438.2
BRCA2	ENST00000614259.2	n.*1233A>G		non_coding_transcript_exon_variant	Exon 23 of 26	2		ENSP00000506251.1
BRCA2	ENST00000614259	n.*1233A>G		3_prime_UTR_variant	Exon 23 of 25	2		ENSP00000506251.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.00000398 AC: 1 AN: 251304 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 135844

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: 0.00000880

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000629 AC: 92 AN: 1461780 Hom.: 0 Cov.: 32 AF XY: 0.0000619 AC XY: 45 AN XY: 727198

Gnomad4 AFR exome AF: 0.00

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: 0.0000818

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 33

ClinVar

Significance: Benign

Submissions summary: Uncertain:4 Benign:7

Revision: reviewed by expert panel

Submissions by phenotype

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

Jul 05, 2011

Sharing Clinical Reports Project (SCRP)

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Jun 18, 2019

Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA)

Significance: Benign

Review Status: reviewed by expert panel

Collection Method: curation

IARC class based on posterior probability from multifactorial likelihood analysis, thresholds for class as per Plon et al. 2008 (PMID: 18951446). Class 1 based on posterior probability = 0.000879 -

Feb 20, 2004

Breast Cancer Information Core (BIC) (BRCA2)

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Jan 19, 2016

Counsyl

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Hereditary cancer-predisposing syndrome Benign:2

Mar 30, 2018

Ambry Genetics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Sep 22, 2017

Color Diagnostics, LLC DBA Color Health

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

BRCA2-related disorder Uncertain:1

Jan 13, 2024

PreventionGenetics, part of Exact Sciences

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

The BRCA2 c.9175A>G variant is predicted to result in the amino acid substitution p.Lys3059Glu. To our knowledge, this variant has not been reported in the literature in affected individuals. This variant is reported in 0.00088% of alleles in individuals of European (Non-Finnish) descent in gnomAD and has varied interpretations in ClinVar, ranging from uncertain to benign, with the ENIGMA expert panel interpreting it as benign (https://www.ncbi.nlm.nih.gov/clinvar/variation/52767/; Supplemental Table 1, Parsons et al. 2019. PubMed ID: 31131967). While we suspect this variant could be benign, at this time its clinical significance is uncertain due to the absence of conclusive functional and genetic evidence. -

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.Lys3059Glu variant was not identified in the literature nor was it identified in the COGR, Cosmic, MutDB, ARUP Laboratories, and Zhejiang Colon Cancer databases. The variant was identified in dbSNP (ID: rs80359174) as “With other allele”; in ClinVar and Clinvitae as likely benign by Invitae, Ambry Genetics, Sharing Clinical Reports Project, and with uncertain significance by GeneDx and Counsyl. In addition, the variant was listed in the BIC database 3X with unknown significance; in LOVD 3.0 database 1X with no classification; in the UMD-LSDB database 2X as uncertain significance with no co-occurrence of other pathogenic variants; and in the BIC Database 3X with unknown significance. The variant was also identified by our laboratory in 2 individuals with breast cancer. Furthermore, the variant was identified in control databases in 1 of 246114 chromosomes at a frequency of 0.000004 (Genome Aggregation Database Feb 27, 2017). It was identified in the European Non-Finnish population in 1 of 111604 chromosomes (freq: 0.000009), but not in the African, Other, Latino, Ashkenazi Jewish, East Asian, European Finnish, and South Asian populations. In silico predicted impact on the protein is uncertain (Karchin_2008). The p.Lys3059 residue is conserved in in mammals but not in more distantly related organisms however computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to the protein; this information is not predictive enough to rule out pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) do not predict a difference in splicing. 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. -

not specified Benign:1

Oct 10, 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.9175A>G (p.Lys3059Glu) results in a conservative amino acid change located in the BRCA2, OB3 domain of 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 4e-06 in 251304 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. Although seen in the literature, to our knowledge, no occurrence of c.9175A>G in individuals affected with Hereditary Breast And Ovarian Cancer Syndrome and no experimental evidence demonstrating its impact on protein function have been reported. At-least two co-occurrences with other pathogenic variant(s) have been ascertained in the BIC database and at our laboratory (BIC database-BRCA2 c.8237_8238delCA, p.Thr2746Serfs; our laboratory-BRCA2 c.8575delC, p.Q2859fsX4), providing supporting evidence for a benign role. Five clinical diagnostic laboratories and an expert panel (ENIGMA) have submitted clinical-significance assessments for this variant to ClinVar after 2014 with a majority consensus as likely benign/benign (n=6, expert panel benign) (VUS, n=1). Based on the evidence outlined above, the variant was classified as likely benign. -

not provided Benign:1

Jun 29, 2020

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is associated with the following publications: (PMID: 19043619, 31131967) -

Hereditary breast ovarian cancer syndrome Benign:1

Nov 18, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.099
BayesDel_addAF	Uncertain	0.13	D
BayesDel_noAF	Uncertain	-0.050
CADD	Benign	19
DANN	Uncertain	0.99
Eigen	Benign	-0.61
Eigen_PC	Benign	-0.62
FATHMM_MKL	Benign	0.097	N
M_CAP	Benign	0.067	D
MetaRNN	Benign	0.13	T;T
MetaSVM	Benign	-0.73	T
PrimateAI	Benign	0.22	T
PROVEAN	Benign	-0.87	N;N
REVEL	Uncertain	0.54
Sift	Benign	0.089	T;T
Sift4G	Benign	0.18	T;T
Vest4		0.22
MutPred		0.49		Loss of ubiquitination at K3059 (P = 0.011);Loss of ubiquitination at K3059 (P = 0.011);
MVP		0.86
MPC		0.035
ClinPred		0.25	T
GERP RS		1.5
gMVP		0.18

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.060		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: rs80359174; hg19: chr13-32954201;