13-32362582-A-G

Position:

chr13-32362582-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 1P and 0B. PP3

The NM_000059.4(BRCA2):c.7865A>G(p.Asn2622Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000105 in 1,614,152 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.000066 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000048 ( 0 hom. )

Consequence

BRCA2
NM_000059.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts P:1U:14

Conservation

PhyloP100: 9.22

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:

BRCA2 (HGNC:):

BRCA2 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 1 ACMG points.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.828

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
BRCA2	NM_000059.4 linkuse as main transcript	c.7865A>G	p.Asn2622Ser	missense_variant	17/27	ENST00000380152.8	NP_000050.3	P51587

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
BRCA2	ENST00000380152.8 linkuse as main transcript	c.7865A>G	p.Asn2622Ser	missense_variant	17/27	5	NM_000059.4	ENSP00000369497.3	P51587
BRCA2	ENST00000530893.7 linkuse as main transcript	c.7496A>G	p.Asn2499Ser	missense_variant	17/27	1		ENSP00000499438.2	A0A590UJI7
BRCA2	ENST00000614259.2 linkuse as main transcript	n.7873A>G		non_coding_transcript_exon_variant	16/26	2		ENSP00000506251.1	A0A7P0TAP7

Frequencies

GnomAD3 genomes

AF:

0.0000657

AC:

AN:

152182

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000241

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:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000279

AC:

AN:

251260

Hom.:

AF XY:

0.0000147

AC XY:

AN XY:

135788

show subpopulations

Gnomad AFR exome

AF:

0.000431

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:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000479

AC:

AN:

1461852

Hom.:

Cov.:

AF XY:

0.00000413

AC XY:

AN XY:

727230

show subpopulations

Gnomad4 AFR exome

AF:

0.000179

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:

8.99e-7

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000657

AC:

AN:

152300

Hom.:

Cov.:

AF XY:

0.0000269

AC XY:

AN XY:

74474

show subpopulations

Gnomad4 AFR

AF:

0.000241

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:

0.00

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000986

Hom.:

Bravo

AF:

0.0000982

ESP6500AA

AF:

0.000227

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.0000576

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Pathogenic:1Uncertain:14

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Uncertain:4

Uncertain significance, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Dec 01, 2020	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Jul 30, 2024	BS1 -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	May 25, 2023	Observed in an individual with breast cancer (Tung et al., 2015); In silico analysis supports that this missense variant does not alter protein structure/function; Also known as 8093A>G; Published functional studies demonstrate decreased homology-directed repair (HDR) activity and increased sensitivity to PARP inhibitors (Hart et al., 2019; Ikegami et al., 2020; Richardson et al., 2021; Iversen et al., 2022); This variant is associated with the following publications: (PMID: 32444794, 33609447, 29884841, 12228710, 35665744, 25186627) -
Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jul 16, 2014	- -

Breast-ovarian cancer, familial, susceptibility to, 2

Pathogenic:1Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Counsyl	Feb 16, 2018	- -
Likely pathogenic, no assertion criteria provided	clinical testing	Sharing Clinical Reports Project (SCRP)	Jan 10, 2013	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Michigan Medical Genetics Laboratories, University of Michigan	Apr 21, 2016	- -

not specified

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Mar 07, 2024	Variant summary: BRCA2 c.7865A>G (p.Asn2622Ser) results in a conservative amino acid change located in the helical domain (IPR015252) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 2.8e-05 in 251260 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.7865A>G has been reported in the literature in at least one individual affected with breast cancer (Tung_2014). This report does 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 observed at our laboratory (BRCA1 c.5324T>G, p.Met1775Arg), providing supporting evidence for a benign role. Multiple publications report conflicting experimental evidence evaluating an impact on protein function that does not allow convincing conclusions about the variant effect. Specifically, some studies through the performance of HDR assays and the MANO-B method (which utilizes BRCA2-deficient cells and PARP inhibitors), determined the variant to be damaging/abnormal (Hart_2019, Ikegami_2020, Richardson_2021). However, a different study utilizing a mouse embryonic stem cell (mESC)-based assay to examine the ability to rescue the lethality of Brca2 null mESC as well as sensitivity to six DNA damaging agents, determined the variant to be functional (Biswas_2020). The following publications have been ascertained in the context of this evaluation (PMID: 33293522, 29884841, 32444794, 33609447, 25186627). ClinVar contains an entry for this variant (Variation ID: 91496). Based on the evidence outlined above, the variant was classified as uncertain significance. -
Uncertain significance, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Nov 23, 2021	- -

Hereditary cancer-predisposing syndrome

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Ambry Genetics	Mar 25, 2024	The p.N2622S variant (also known as c.7865A>G), located in coding exon 16 of the BRCA2 gene, results from an A to G substitution at nucleotide position 7865. The asparagine at codon 2622 is replaced by serine, an amino acid with highly similar properties. This alteration was reported in a woman with breast cancer diagnosed under age 50 from a cohort of 2158 women who underwent multi-gene panel testing for hereditary breast cancer (Tung N et al. Cancer. 2015 Jan;121(1):25-33). This variant was also identified in a cohort of 3,579 African males diagnosed with prostate cancer who underwent multi-gene panel testing of 19 DNA repair and cancer predisposition genes (Matejcic M et al. JCO Precis Oncol, 2020 Jan;4:32-43). This variant was non-functional in a homology-directed DNA repair (HDR) assay (Hart SN et al. Genet. Med. 2018 Jun;21(1):71-80; Richardson ME et al. Am J Hum Genet, 2021 03;108:458-468). This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Based on the available evidence, the clinical significance of this alteration remains unclear. -
Uncertain significance, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Sep 18, 2021	This missense variant replaces asparagine with serine at codon 2622 of the BRCA2 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). Functional studies have reported conflicting impacts of this variant on BRCA2. Two studies have reported that this variant impacts BRCA2 homology-directed repair activity and in the rescue of PARP inhibitor and carboplatin sensitivities in BRCA2-deficient cells (PMID: 29884841, 32444794). However, a third study reported that this variant does not impact the rescue of cell viability and partially impacts drug sensitivity in Brca2-deficient mouse embryonic stem cell assays (PMID: 33293522). This variant has been observed in an individual affected with breast cancer (PMID: 25186627). This variant also has been reported in 1 individual age 70 years or older without cancer in the FLOSSIES database and identified in 8/282658 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. -

Medulloblastoma;C0346153:Familial cancer of breast;C0376358:Malignant tumor of prostate;C1838457:Fanconi anemia complementation group D1;C2675520:Breast-ovarian cancer, familial, susceptibility to, 2;C2751641:Glioma susceptibility 3;C3150546:Pancreatic cancer, susceptibility to, 2;CN033288:Wilms tumor 1

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Mar 27, 2022

- -

BRCA2-related cancer predisposition

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

All of Us Research Program, National Institutes of Health

Aug 23, 2024

This missense variant replaces asparagine with serine at codon 2622 of the BRCA2 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function. Functional studies have reported conflicting impacts of this variant on BRCA2. Two studies have reported that this variant impacts BRCA2 homology-directed repair activity and in the rescue of PARP inhibitor and carboplatin sensitivities in BRCA2-deficient cells (PMID: 29884841, 32444794). However, a third study reported that this variant does not impact the rescue of cell viability and partially impacts drug sensitivity in Brca2-deficient mouse embryonic stem cell assays (PMID: 33293522). A multifactorial analysis has reported a likelihood ratio for pathogenicity based on personal and family history of 5.955 from log(LR)=0.774858177 (PMID: 31853058). This variant has been observed in an individual affected with breast cancer (PMID: 25186627). This variant also has been reported in 1 individual age 70 years or older without cancer in the FLOSSIES database (https://whi.color.com/variant/13-32936719-A-G) and identified in 8/282658 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. -

Familial cancer of breast

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Baylor Genetics

Dec 03, 2023

- -

Hereditary breast ovarian cancer syndrome

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Dec 22, 2023

This sequence change replaces asparagine, which is neutral and polar, with serine, which is neutral and polar, at codon 2622 of the BRCA2 protein (p.Asn2622Ser). This variant is present in population databases (rs142899125, gnomAD 0.03%). This missense change has been observed in individual(s) with breast cancer (PMID: 25186627). ClinVar contains an entry for this variant (Variation ID: 91496). Advanced modeling performed at Invitae incorporating data from internal and/or published experimental studies (PMID: 33609447) did not meet the statistical confidence thresholds required to predict the impact of this variant on BRCA2 function. Experimental studies are conflicting or provide insufficient evidence to determine the effect of this variant on BRCA2 function (PMID: 29884841, 32444794, 33293522, 33609447). RNA analysis performed to evaluate the impact of this missense change on mRNA splicing indicates it does not significantly alter splicing (Invitae). 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. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.28

BayesDel_addAF

Benign

-0.0054

BayesDel_noAF

Uncertain

0.070

CADD

Uncertain

DANN

Uncertain

1.0

Eigen

Pathogenic

0.96

Eigen_PC

Pathogenic

0.91

FATHMM_MKL

Pathogenic

0.97

M_CAP

Pathogenic

0.33

MetaRNN

Pathogenic

0.83

D;D

MetaSVM

Pathogenic

0.96

PrimateAI

Uncertain

0.56

PROVEAN

Benign

-1.3

N;N

REVEL

Pathogenic

0.76

Sift

Pathogenic

0.0

D;D

Sift4G

Pathogenic

0.0

D;D

Vest4

0.89

MVP

0.97

MPC

0.16

ClinPred

0.58

GERP RS

5.7

gMVP

0.74

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

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