rs80359069

chr13-32363417-G-Achr13-32363417-G-Cchr13-32363417-G-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.8215G>A(p.Val2739Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000192 in 1,614,052 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/18 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. V2739L) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.000085 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000012 (0 hom.)
• Consequence: BRCA2 NM_000059.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:9 B:11
• Conservation: PhyloP100: 1.72

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=0.12431899).
• BP6: Variant 13-32363417-G-A is Benign according to our data. Variant chr13-32363417-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 52529.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=7, Likely_benign=6, Benign=2}. Variant chr13-32363417-G-A is described in Lovd as [Likely_benign]. Variant chr13-32363417-G-A is described in Lovd as [Benign].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
BRCA2	NM_000059.4	c.8215G>A	p.Val2739Ile	missense_variant	18/27	ENST00000380152.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
BRCA2	ENST00000380152.8	c.8215G>A	p.Val2739Ile	missense_variant	18/27	5	NM_000059.4	A2

Frequencies

GnomAD3 genomes AF: 0.0000854 AC: 13 AN: 152188 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000851

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: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.0000123 AC: 18 AN: 1461864 Hom.: 0 Cov.: 31 AF XY: 0.0000110 AC XY: 8 AN XY: 727230

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000180

Gnomad4 OTH exome AF: 0.000248

GnomAD4 genome AF: 0.0000854 AC: 13 AN: 152188 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 74356

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.000851

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

Bravo AF: 0.0000416

ExAC AF: 0.0000165 AC: 2

Asia WGS AF: 0.000577 AC: 2 AN: 3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:9 Benign:11

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Breast-ovarian cancer, familial, susceptibility to, 2 Uncertain:5 Benign:1

Uncertain significance, no assertion criteria provided	clinical testing	Breast Cancer Information Core (BIC) (BRCA2)	May 29, 2002	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Baylor Genetics	Apr 13, 2019	This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868]. This variant has been previously reported as a patient with breast or ovarian cancer [PMID 25556971] -
Uncertain significance, no assertion criteria provided	clinical testing	Sharing Clinical Reports Project (SCRP)	Jan 13, 2012	- -
Likely benign, criteria provided, single submitter	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	Sep 21, 2015	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Dec 19, 2017	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -
Uncertain significance, criteria provided, single submitter	clinical testing	Counsyl	Sep 08, 2017	- -

not provided Uncertain:1 Benign:4

Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Sep 20, 2021	This variant is associated with the following publications: (PMID: 24094589, 26580448, 26689913, 25348012, 21702907, 19043619, 21218378, 25682074, 25556971) -
Likely benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics Laboratory, Department of Pathology, Netherlands Cancer Institute	-	- -
Uncertain significance, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	May 03, 2023	The BRCA2 c.8215G>A; p.Val2739Ile variant (rs80359069) is reported in the literature in individuals affected with breast and/or ovarian cancer (Carney 2010, Trujillano 2015). This variant is reported as uncertain significance or likely benign by multiple laboratories in ClinVar (Variation ID: 52529), and is absent from the Genome Aggregation Database, indicating it is not a common polymorphism. Computational analyses are uncertain whether this variant is neutral or deleterious (REVEL: 0.268) Functional analyses of the variant protein show near WT levels of repair activity and mouse embryonic stem cell-based assay shows functional cell survival and drug sensitivity (Biswas 2020, Karchin 2008). Due to limited information, the clinical significance of the p.Val2739Ile variant is uncertain at this time. References: Biswas K et al. A computational model for classification of BRCA2 variants using mouse embryonic stem cell-based functional assays. NPJ Genom Med. 2020 Dec 8;5(1):52. PMID: 33293522. Carney ME et al. Detection of BRCA1 and BRCA2 mutations in a selected Hawaii population. Hawaii Med J. 2010 Nov;69(11):268-71. PMID: 21218378. Karchin R et al. Classifying Variants of Undetermined Significance in BRCA2 with protein likelihood ratios. Cancer Inform. 2008;6:203-16. PMID: 19043619. Trujillano D et al. Next-generation sequencing of the BRCA1 and BRCA2 genes for the genetic diagnostics of hereditary breast and/or ovarian cancer. J Mol Diagn. 2015 Mar;17(2):162-70. PMID: 25556971. -
Likely benign, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Feb 18, 2020	- -

Hereditary cancer-predisposing syndrome Uncertain:1 Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Oct 05, 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	Jul 23, 2015	- -
Uncertain significance, criteria provided, single submitter	curation	Sema4, Sema4	Dec 17, 2021	- -

BRCA2-related condition Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

May 23, 2023

The BRCA2 c.8215G>A variant is predicted to result in the amino acid substitution p.Val2739Ile. This variant has been reported in an individuals with breast cancer and in individuals undergoing hereditary cancer testing (Table 3, Trujillano et al. 2015. PubMed ID: 25556971; Table 1, Carney et al. 2010. PubMed ID: 2128378; Supplement, Hondow et al. 2011. PubMed ID: 21702907; Supplement, Tung et al. 2015. PubMed ID: 25186627; Table S2, Wong-brown et al. 2015. PubMed ID: 25682074). Experimental evaluation using a homology-directed repair assay was inconclusive (Table S2, Karchin et al. 2008. PubMed ID: 19043619). This variant has not been reported in a large population database (http://gnomad.broadinstitute.org), and has conflicting interpretations of pathogenicity ranging from benign to uncertain in the ClinVar database (https://www.ncbi.nlm.nih.gov/clinvar/variation/52529/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Fanconi anemia complementation group D1 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 28, 2017

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Apr 02, 2021

Variant summary: BRCA2 c.8215G>A (p.Val2739Ile) results in a conservative amino acid change located in the OB1 domain (IPR015187) of the encoded protein sequence. Five of five in-silico tools predict a benign effect of the variant on protein function. The variant was absent in 249656 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.8215G>A, has been reported in the literature in individuals affected with Hereditary Breast and Ovarian Cancer without strong evidence for pathogenicity (Carney_2010, Trujillano_2015, Wong-Brown_2015, Tung_2015). These reports 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 BIC database and observed at our laboratory (BRCA2 c.6486_6489delACAA , p.Lys2162fsX5 at our laboratory; BRCA1 c.81-2delA in BIC database), providing supporting evidence for a benign role. At least two publications report experimental evidence evaluating an impact on protein function. These results showed no damaging effect of this variant on homology directed repair activity and in a mouse embryonic stem cell-based cell survival plus drug sensitivity assay (Karchin_2008, Biswas_2020). Eleven 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 (likely benign/benign, n=6; VUS, n=5). Some submitters cite overlapping evidence utilized in the context of this evaluation. Based on the evidence outlined above, the variant was classified as benign. -

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

May 03, 2022

- -

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.Val2739Ile variant was identified in 10 of 3474 proband chromosomes (frequency: 0.003) from Australian, Polish, German and Hawaiian individuals or families with triple negative breast cancer or HBOC (Wong-Brown 2015 25682074, Lai 2015, Hondow 2011 21702907, Carney 2010 21218378, Trujillano 2015 25556971, Bosdet 2013 24094589). In a computational method that produces a probabilistic likelihood ratio predictive of impaired protein function, the variant was found to be neutral consistent with previously reported functional data related to homology directed repair (Karchin 2008). The variant was also identified in dbSNP (ID: rs80359069) “With Likely benign, Uncertain significance, other allele”, ClinVar (classified benign by Invitae, likely benign by Ambry Genetics, GeneDx, Quest Diagnostics Nichols Institute San Juan Capistrano, and uncertain significance by Laboratory Corporation of America, SCRP and BIC), Clinvitae (5x), LOVD 3.0 (10x as predicted neutral and unknown function), UMD-LSDB (13x unclassified), BIC Database (6x unknown clinical importance, classification pending), and was not identified in Cosmic, MutDB, ARUP Laboratories, or the Zhejiang Colon Cancer Database. The variant was identified in control databases in 2 of 244404 chromosomes at a frequency of 0.000008 (Genome Aggregation Database Feb 27, 2017), in the East Asian population in 2 of 17246 chromosomes (freq: 0.0001), while not observed in the African, Other, Latino, European Non-Finnish, Ashkenazi Jewish, European Finnish and South Asian populations. The p.Val2739 residue is not conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of the p.Val2739Ile variant impacting the protein; however, 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 although we would lean towards a more benign role for this variant. This variant is classified as likely benign. -

Hereditary breast ovarian cancer syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 31, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.066
BayesDel_addAF	Benign	-0.17	T
BayesDel_noAF	Benign	-0.26
Cadd	Benign	7.7
Dann	Benign	0.87
Eigen	Benign	-0.88
Eigen_PC	Benign	-0.72
FATHMM_MKL	Benign	0.53	D
M_CAP	Benign	0.032	D
MetaRNN	Benign	0.12	T;T
MetaSVM	Benign	-0.92	T
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.24	T
PROVEAN	Benign	0.19	N;N
REVEL	Benign	0.27
Sift	Benign	0.16	T;T
Sift4G	Benign	0.17	T;T
Vest4		0.24
MutPred		0.47		Loss of methylation at R2744 (P = 0.1524);Loss of methylation at R2744 (P = 0.1524);
MVP		0.68
MPC		0.019
ClinPred		0.038	T
GERP RS		2.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
gMVP		0.21

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: rs80359069; hg19: chr13-32937554;