rs80359103

Positions:

chr13-32370986-A-G

Variant summary

Our verdict is Likely benign. Variant got -1 ACMG points: 0P and 1B. BP4

The NM_000059.4(BRCA2):c.8518A>G(p.Ile2840Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000867 in 1,614,030 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 Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000082 ( 0 hom. )

Consequence

BRCA2
NM_000059.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:15

Conservation

PhyloP100: 1.13

Variant links:

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -1 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.31261486).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
BRCA2	NM_000059.4 linkuse as main transcript	c.8518A>G	p.Ile2840Val	missense_variant	20/27	ENST00000380152.8	NP_000050.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
BRCA2	ENST00000380152.8 linkuse as main transcript	c.8518A>G	p.Ile2840Val	missense_variant	20/27	5	NM_000059.4	ENSP00000369497	A2

Frequencies

GnomAD3 genomes

AF:

0.0000131

AC:

AN:

152184

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000192

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:

0.00000796

AC:

AN:

251176

Hom.:

AF XY:

0.0000147

AC XY:

AN XY:

135732

show subpopulations

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:

0.0000176

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000821

AC:

AN:

1461846

Hom.:

Cov.:

AF XY:

0.0000110

AC XY:

AN XY:

727224

show subpopulations

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:

0.00000899

Gnomad4 OTH exome

AF:

0.0000331

GnomAD4 genome

AF:

0.0000131

AC:

AN:

152184

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74348

show subpopulations

Gnomad4 AFR

AF:

0.0000241

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000192

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000688

Hom.:

Bravo

AF:

0.0000302

ExAC

AF:

0.0000165

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:15

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Breast-ovarian cancer, familial, susceptibility to, 2

Uncertain:4

Uncertain significance, criteria provided, single submitter	clinical testing	All of Us Research Program, National Institutes of Health	Mar 23, 2023	This missense variant replaces isoleucine with valine at codon 2840 of the BRCA2 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in two individuals affected with breast cancer and one of whom also has a pathogenic BRCA2 co-variant and in a suspected hereditary breast and ovarian cancer family (PMID: 15876480, 16826315, 34917121) This variant also has been detected in a breast cancer case-control meta-analysis in 1/60463 cases and 1/53461 unaffected individuals (PMID: 33471991; Leiden Open Variation Database DB-ID BRCA2_000339). This variant has been identified in 3/282570 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. -
Uncertain significance, no assertion criteria provided	clinical testing	Breast Cancer Information Core (BIC) (BRCA2)	Feb 20, 2004	- -
Uncertain significance, criteria provided, single submitter	clinical testing	KCCC/NGS Laboratory, Kuwait Cancer Control Center	Oct 09, 2024	This sequence change replaces isoleucine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 2840 of the BRCA2 protein (p.Ile2840Val). This amino acid position is not well conserved .This variant is present in population databases (rs80359103, gnomAD 0.002%). This missense change has been observed in individual(s) with BRCA2-related conditions (PMID: 15876480, 16826315, 24916970, 35264596). This variant is also known as 8746A>G. ClinVar contains an entry for this variant (Variation ID: 52609). In addition, the in silico prediction for this alteration is inconclusive. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -
Uncertain significance, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -

not specified

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Mar 20, 2024	Variant summary: BRCA2 c.8518A>G (p.Ile2840Val) results in a conservative amino acid change located in the Tower 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 8e-06 in 251176 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.8518A>G has been reported in the literature in individuals affected with Hereditary Breast And Ovarian Cancer Syndrome, and has also been observed in the control cohorts from multiple studies (examples, Buzolin_2017, Dorling_2021, Guindalini_2022, Karchin_2008, Li_2018, Peixoto_2014, Peixoto_2006, Su_2021). These report(s) do not provide unequivocal conclusions about association of the variant with Hereditary Breast And Ovarian Cancer Syndrome. At-least one co-occurrence with another pathogenic variant(s) has been reported (Salzaar_2006, BRCA2 c.8639_8643del, p.Thr2880fs), providing supporting evidence for a benign role. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 28651617, 33471991, 35264596, 19043619, 30078507, 24916970, 16826315, 15876480, 34917121). ClinVar contains an entry for this variant (Variation ID: 52609). Based on the evidence outlined above, the variant was classified as VUS-possibly benign. -
Uncertain significance, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	May 20, 2021	- -

not provided

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Jun 12, 2017	This variant is denoted BRCA2 c.8518A>G at the cDNA level, p.Ile2840Val (I2840V) at the protein level, and results in the change of an Isoleucine to a Valine (ATA>GTA). Using alternate nomenclature, this variant would be defined as BRCA2 8746A>G. This variant has been observed in individuals of Portugese ancestry with a personal and/or family history of breast and/or ovarian cancer, and was reported to co-occur with BRCA2 c.8482A>G (p.Ile2828Val) in at least one individual (Peixoto 2006, Peixoto 2014). Additionally, Salazar et al. (2006) found this variant to co-occur with a BRCA2 frameshift variant, described as pathogenic, in an individual with a personal and/or family history of bilateral breast cancer. BRCA2 Ile2840Val was not observed at a significant allele frequency in large population cohorts (NHLBI Exome Sequencing Project, The 1000 Genomes Consortium 2015, Lek 2016). Since Isoleucine and Valine share similar properties, this is considered a conservative amino acid substitution. BRCA2 Ile2840Val occurs at a position where amino acids with properties similar to Isoleucine are tolerated across species and is located within the DNA binding domain (Yang 2002). In silico analyses are inconsistent regarding the effect this variant may have on protein structure and function. Based on currently available information, it is unclear whether BRCA2 Ile2840Val is pathogenic or benign. We consider it to be a variant of uncertain significance. -
Uncertain significance, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Apr 01, 2022	The p.Ile2840Val variant in BRCA2 has been reported in at least 3 individuals with BRCA2-associated cancers; 2 of these individuals were also heterozygous for additional BRCA2 variants (Salazar 2006 PMID: 15876480, Peixoto 2006 PMID: 16826315, Karchin 2008 PMID: 19043619). It has also been identified in 0.002% (3/128296) of European chromosomes by gnomAD (http://gnomad.broadinstitute.org). This variant has also been reported in ClinVar (Variation ID 52609). 5 mammals (Golden hamster, pika, weddell seal, tenrec, aardvark, platypus) and many bird species carry a Valine at this position despite high nearby amino acid conservation. In addition, computational prediction tools predict that this variant does not impact the protein. In summary, while the clinical significance of this variant is uncertain, these data suggest that it is more likely to be benign. ACMG/AMP Criteria applied: PM2_P, PS4_P, BP4. -

Hereditary cancer-predisposing syndrome

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Ambry Genetics	Dec 08, 2023	The p.I2840V variant (also known as c.8518A>G), located in coding exon 19 of the BRCA2 gene, results from an A to G substitution at nucleotide position 8518. The isoleucine at codon 2840 is replaced by valine, an amino acid with highly similar properties. This alteration has been detected in a breast cancer family from Spain, which also carried a reported BRCA2 mutation, 8873del4 (Salazar R et al. Cancer Lett. 2006; 233:172-7), and in a breast/ovarian cancer family from Portugal, which also carried a second nearby alteration, p.I2828V, in the BRCA2 gene (Peixoto A et al. Fam Cancer. 2006; 5:379-87). Additionally, this alteration was identified in multiple individuals diagnosed with breast cancer (Su Y et al. Front Genet, 2021 Nov;12:674094; Guindalini RSC et al. Sci Rep, 2022 Mar;12:4190; Yao L et al. J Hum Genet, 2022 Nov;67:639-642). This amino acid position is not well conserved in available vertebrate species, and valine is the reference amino acid in several species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -
Uncertain significance, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Feb 15, 2023	This missense variant replaces isoleucine with valine at codon 2840 of the BRCA2 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in two individuals affected with breast cancer and one of whom also has a pathogenic BRCA2 co-variant and in a suspected hereditary breast and ovarian cancer family (PMID: 15876480, 16826315, 34917121) This variant also has been detected in a breast cancer case-control meta-analysis in 1/60463 cases and 1/53461 unaffected individuals (PMID: 33471991; Leiden Open Variation Database DB-ID BRCA2_000339). This variant has been identified in 3/282570 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. -

Hereditary breast ovarian cancer syndrome

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	This sequence change replaces isoleucine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 2840 of the BRCA2 protein (p.Ile2840Val). This variant is present in population databases (rs80359103, gnomAD 0.002%). This missense change has been observed in individual(s) with BRCA2-related conditions (PMID: 15876480, 16826315, 24916970, 35264596). This variant is also known as 8746A>G. ClinVar contains an entry for this variant (Variation ID: 52609). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt BRCA2 protein function with a negative predictive value of 95%. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -
Uncertain significance, criteria provided, single submitter	clinical testing	Institute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C.	Nov 22, 2022	- -

BRCA2-related disorder

Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Jul 17, 2024

The BRCA2 c.8518A>G variant is predicted to result in the amino acid substitution p.Ile2840Val. This variant (also reported as c.8746A>G) has been identified in individuals with a history of breast and/or ovarian cancer (Table 2, Peixoto et al. 2015. PubMed ID: 24916970; Salazar et al. 2006. PubMed ID: 15876480; Peixoto et al. 2006. PubMed ID: 16826315). In one individual, an additional pathogenic BRCA2 variant was also identified (Salazar et al. 2006. PubMed ID: 15876480). Computational prediction algorithms specific to BRCA2 suggest this variant’s impact on protein activity is neutral (Supplemental Table 1, Karchin et al. 2008. PubMed ID: 19043619). This variant is reported in 0.0023% of alleles in individuals of European (Non-Finnish) descent in gnomAD and is listed in ClinVar as a variant of uncertain significance (https://www.ncbi.nlm.nih.gov/clinvar/variation/52609/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Malignant tumor of prostate

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein

Oct 28, 2022

ACMG classification criteria: PM2 supporting, BP4 supporting -

Familial cancer of breast

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Baylor Genetics

Mar 29, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.063

BayesDel_addAF

Uncertain

0.085

BayesDel_noAF

Benign

-0.10

CADD

Benign

DANN

Benign

0.93

Eigen

Benign

-0.47

Eigen_PC

Benign

-0.34

FATHMM_MKL

Benign

0.49

M_CAP

Benign

0.0088

MetaRNN

Benign

0.31

T;T

MetaSVM

Benign

-1.0

MutationTaster

Benign

0.65

N;N

PrimateAI

Benign

0.33

PROVEAN

Benign

-0.26

N;N

REVEL

Benign

0.23

Sift

Benign

0.43

T;T

Sift4G

Benign

0.90

T;T

Vest4

0.75

MutPred

0.78

Loss of sheet (P = 0.1158);Loss of sheet (P = 0.1158);

MVP

0.75

MPC

0.021

ClinPred

0.054

GERP RS

1.4

gMVP

0.25

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over