rs80358417

Positions:

chr13-32332722-A-G

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 0P and 3B. BP4_ModerateBP6

The NM_000059.4(BRCA2):c.1244A>G(p.His415Arg) 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 1,613,168 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. H415H) has been classified as Likely benign.

Frequency

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

Exomes 𝑓: 0.000020 ( 0 hom. )

Consequence

BRCA2
NM_000059.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:10B:7

Conservation

PhyloP100: 0.0460

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 -3 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.20460224).

BP6

Variant 13-32332722-A-G is Benign according to our data. Variant chr13-32332722-A-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 51090.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=4, Uncertain_significance=8}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
BRCA2	NM_000059.4 linkuse as main transcript	c.1244A>G	p.His415Arg	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 linkuse as main transcript	c.1244A>G	p.His415Arg	missense_variant	10/27	5	NM_000059.4	ENSP00000369497	A2

Frequencies

GnomAD3 genomes

AF:

0.0000131

AC:

AN:

152196

Hom.:

Cov.:

show subpopulations

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:

0.0000294

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.00000802

AC:

AN:

249452

Hom.:

AF XY:

0.0000148

AC XY:

AN XY:

135102

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:

0.00000884

Gnomad OTH exome

AF:

0.000166

GnomAD4 exome

AF:

0.0000198

AC:

AN:

1460972

Hom.:

Cov.:

AF XY:

0.0000220

AC XY:

AN XY:

726738

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.000126

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000198

Gnomad4 OTH exome

AF:

0.0000331

GnomAD4 genome

AF:

0.0000131

AC:

AN:

152196

Hom.:

Cov.:

AF XY:

0.0000269

AC XY:

AN XY:

74352

show subpopulations

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:

0.0000294

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000823

Hom.:

Bravo

AF:

0.0000302

EpiCase

AF:

0.000164

EpiControl

AF:

0.00

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:10Benign:7

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Breast-ovarian cancer, familial, susceptibility to, 2

Uncertain:3Benign:3

Uncertain significance, no assertion criteria provided	clinical testing	Breast Cancer Information Core (BIC) (BRCA2)	Dec 23, 2003	- -
Likely benign, criteria provided, single submitter	clinical testing	All of Us Research Program, National Institutes of Health	Aug 23, 2023	- -
Likely benign, no assertion criteria provided	clinical testing	Department of Pathology and Laboratory Medicine, Sinai Health System	-	The BRCA2 p.His415Arg variant was identified in 2 of 1506 proband chromosomes (frequency: 0.001) from individuals or families with breast or ovarian cancer (Alemar 2017, Wong 2015). The variant was also identified in large population study by Momozawa (2018) in 5 of 14102 female chromosomes (frequency: 0.0004), and 7 in 22482 female control chromosomes (frequency: 0.0003) and 4 in 24980 male control chromosomes (frequency: 0.0002). The variant was also identified in dbSNP (ID: rs80358417) as "With Uncertain significance allele", ClinVar (classified as likely benign by Invitae and Color; as uncertain significance by six submitters), LOVD 3.0 (6x), and UMD-LSDB (9x as likely neutral). In UMD the variant was identified with a co-occurring pathogenic BRCA1 variant (c.3979C>T(p.Gln1327X)), increasing the likelihood that the p.His415Arg variant does not have clinical significance. The variant was also identified by our laboratory in 1 individual with pancreatic cancer, co-occurring with a pathogenic BRCA1 variant (c.5278-?_5592+?del, p.Ile1760_His1862delins37), further increasing the likelihood this variant has little clinical significance. The variant was identified in control databases in 5 of 275910 chromosomes at a frequency of 0.00002 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: Other in 1 of 6428 chromosomes (freq: 0.0002), European in 4 of 126226 chromosomes (freq: 0.00003); it was not observed in the African, Latino, Ashkenazi Jewish, East Asian, Finnish, and South Asian populations. The p.His415 residue is conserved in mammals but not in more distantly related organisms however four out of five 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) 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. -
Uncertain significance, criteria provided, single submitter	clinical testing	Genetics and Molecular Pathology, SA Pathology	Dec 31, 2019	Insufficient evidence -
Uncertain significance, criteria provided, single submitter	clinical testing	Counsyl	Mar 23, 2016	- -
Likely benign, no assertion criteria provided	clinical testing	Department of Medical and Surgical Sciences, University of Bologna	Sep 01, 2023	BP1(Strong)+BP5(Moderate) according to ACMG/AMP classification guidelines specified for BRCA1 & BRCA2 (Classification Criteria V1.0.0 2023-09-08 - https://cspec.genome.network/cspec/ui/svi/affiliation/50087) (PMID: 38160042) -

Hereditary cancer-predisposing syndrome

Uncertain:2Benign:2

Uncertain significance, criteria provided, single submitter	clinical testing	Ambry Genetics	Jun 07, 2024	The p.H415R variant (also known as c.1244A>G), located in coding exon 9 of the BRCA2 gene, results from an A to G substitution at nucleotide position 1244. The histidine at codon 415 is replaced by arginine, an amino acid with highly similar properties. This alteration has been reported in a cohort of 418 Brazilian individuals who met NCCN genetic testing guidelines for hereditary breast and ovarian cancer (Alemar B et al. PLoS One, 2017 Nov;12:e0187630). This alteration has also been identified in individuals diagnosed with breast and/or ovarian cancer (Wong-Brown MW et al. Breast Cancer Res Treat, 2015 Feb;150:71-80; Zuntini R et al. Front Genet, 2018 Sep;9:378; Santonocito C et al. Cancers (Basel), 2020 May;12:). This amino acid position is not well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Based on the available evidence, the clinical significance of this variant remains unclear. -
Likely benign, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Sep 14, 2017	- -
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). -
Uncertain significance, criteria provided, single submitter	curation	Sema4, Sema4	Sep 19, 2021	- -

not specified

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Mendelics	May 04, 2022	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Oct 03, 2022	Variant summary: BRCA2 c.1244A>G (p.His415Arg) 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 8e-06 in 249452 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.1244A>G has been reported in the literature as a VUS in individuals undergoing testing for Breast and/or Ovarian Cancer (example, Alemar_2017, Momozawa_2018, Wong-Brown_2015, Zuntini_2018). 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) have been reported in the UMD database (BRCA1 c.3979C>T, p.Gln1327Ter), providing supporting evidence for a benign role. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Eight 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 (VUS, n=6; likely benign, n=2). Based on the evidence outlined above, the variant was classified as uncertain significance. -

not provided

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Aug 08, 2024	Observed in individuals with breast and/or ovarian cancer, pancreatic cancer, as well as, unaffected controls (PMID: 25682074, 29161300, 30287823, 30254663, 32980694, 32438681, 33471991); Published functional studies demonstrate homologous recombination activity similar to wild-type (PMID: 37731132); In silico analysis indicates that this missense variant does not alter protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); Also known as 1472A>G; This variant is associated with the following publications: (PMID: 10923033, 25682074, 29161300, 30254663, 32438681, 30287823, 32980694, 29884841, 31131967, 32377563, 33471991, 31853058, 34597585, 34271781, 36775216, 35534704, 37937776, 36243179, 37731132) -
Uncertain significance, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Nov 06, 2020	- -

Breast and/or ovarian cancer

Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

Foulkes Cancer Genetics LDI, Lady Davis Institute for Medical Research

Jan 29, 2014

- -

Hereditary breast ovarian cancer syndrome

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 25, 2024

- -

EBV-positive nodal T- and NK-cell lymphoma

Benign:1

Likely benign, no assertion criteria provided

research

Department of Clinical Pathology, School of Medicine, Fujita Health University

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.074

BayesDel_addAF

Benign

-0.055

BayesDel_noAF

Benign

-0.32

CADD

Benign

0.094

DANN

Benign

0.59

Eigen

Benign

-0.77

Eigen_PC

Benign

-0.93

FATHMM_MKL

Benign

0.057

M_CAP

Benign

0.041

MetaRNN

Benign

0.20

T;T

MetaSVM

Benign

-0.91

MutationTaster

Benign

1.0

N;N

PrimateAI

Benign

0.26

PROVEAN

Benign

-1.5

N;N

REVEL

Benign

0.19

Sift

Benign

0.050

D;D

Sift4G

Benign

0.27

T;T

Vest4

0.34

MVP

0.85

MPC

0.022

ClinPred

0.074

GERP RS

-1.4

gMVP

0.12

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