NM_000059.4:c.323A>G

Variant summary

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

The NM_000059.4(BRCA2):​c.323A>G​(p.Asn108Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000571 in 1,576,836 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 Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 32)
Exomes 𝑓: 0.0000049 ( 0 hom. )

Consequence

BRCA2
NM_000059.4 missense

Scores

1
15

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:14B:2

Conservation

PhyloP100: 0.857
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]

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=0.083491504).
BP6
Variant 13-32325082-A-G is Benign according to our data. Variant chr13-32325082-A-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 51430.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=10, Likely_benign=2}.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
BRCA2NM_000059.4 linkc.323A>G p.Asn108Ser missense_variant Exon 4 of 27 ENST00000380152.8 NP_000050.3 P51587

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
BRCA2ENST00000380152.8 linkc.323A>G p.Asn108Ser missense_variant Exon 4 of 27 5 NM_000059.4 ENSP00000369497.3 P51587
BRCA2ENST00000530893 linkc.-47A>G 5_prime_UTR_variant Exon 4 of 27 1 ENSP00000499438.2 A0A590UJI7
BRCA2ENST00000614259.2 linkn.323A>G non_coding_transcript_exon_variant Exon 3 of 26 2 ENSP00000506251.1 A0A7P0TAP7

Frequencies

GnomAD3 genomes
AF:
0.0000131
AC:
2
AN:
152196
Hom.:
0
Cov.:
32
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:
0.000193
Gnomad SAS
AF:
0.000207
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.00
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.0000319
AC:
8
AN:
250556
Hom.:
0
AF XY:
0.0000295
AC XY:
4
AN XY:
135466
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.000435
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:
0.00000491
AC:
7
AN:
1424640
Hom.:
0
Cov.:
28
AF XY:
0.00000563
AC XY:
4
AN XY:
710922
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.000152
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00
Gnomad4 OTH exome
AF:
0.0000169
GnomAD4 genome
AF:
0.0000131
AC:
2
AN:
152196
Hom.:
0
Cov.:
32
AF XY:
0.0000269
AC XY:
2
AN XY:
74358
show subpopulations
Gnomad4 AFR
AF:
0.00
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.000193
Gnomad4 SAS
AF:
0.000207
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.00
Gnomad4 OTH
AF:
0.00
Bravo
AF:
0.0000567
ExAC
AF:
0.0000247
AC:
3

ClinVar

Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:14Benign:2
Revision: criteria provided, conflicting classifications
LINK: link

Submissions by phenotype

Breast-ovarian cancer, familial, susceptibility to, 2 Uncertain:5
Oct 07, 2013
Sharing Clinical Reports Project (SCRP)
Significance: Uncertain significance
Review Status: no assertion criteria provided
Collection Method: clinical testing

- -

Feb 08, 2016
Counsyl
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Jun 22, 1998
Breast Cancer Information Core (BIC) (BRCA2)
Significance: Uncertain significance
Review Status: no assertion criteria provided
Collection Method: clinical testing

- -

Jan 13, 2018
Illumina Laboratory Services, Illumina
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -

Dec 01, 2023
All of Us Research Program, National Institutes of Health
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

This missense variant replaces asparagine with serine at codon 108 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 one individual each affected with breast cancer, ovarian cancer and ductal carcinoma in situ (PMID: 10755399, 28338653, 30606148) and a suspected HBOC family (PMID: 21702907). In a large breast cancer case-control meta-analysis conducted by the BRIDGES consortium, this variant was reported in 5/60466 cases and 2/53461 unaffected controls (p-value=0.459) (PMID: 33471991; Leiden Open Variation Database DB-ID BRCA2_007696). This variant has been identified in 8/250556 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. -

not provided Uncertain:2
Jul 26, 2024
Quest Diagnostics Nichols Institute San Juan Capistrano
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The BRCA2 c.323A>G (p.Asn108Ser) variant has been reported in the published literature in individuals/families with history of breast and/or ovarian cancer (PMID: 35918668 (2022), 30606148 (2019), 28338653 (2017), 10755399 (2000)). In a large scale breast cancer association study, the variant was observed individuals with breast cancer, as well as in reportedly healthy individuals (PMID: 33471991 (2021), see also LOVD (http://databases.lovd.nl/shared/genes/BRCA2)). The frequency of this variant in the general population, 0.00044 (8/18378 chromosomes in East Asian subpopulation (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is higher than would generally be expected for pathogenic variants in this gene. Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded predictions that this variant is benign. Based on the available information, we are unable to determine the clinical significance of this variant. -

May 09, 2023
GeneDx
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

In silico analysis supports that this missense variant does not alter protein structure/function; Also known as 551A>G; This variant is associated with the following publications: (PMID: 21702907, 24817641, 32467295, 30606148) -

Familial cancer of breast Uncertain:2
Oct 02, 2023
Baylor Genetics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

-
Center for Precision Medicine, Meizhou People's Hospital
Significance: Uncertain significance
Review Status: no assertion criteria provided
Collection Method: literature only

- -

Hereditary cancer-predisposing syndrome Uncertain:1Benign:1
Sep 30, 2021
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. -

Mar 21, 2023
Color Diagnostics, LLC DBA Color Health
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

This missense variant replaces asparagine with serine at codon 108 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 one individual each affected with breast cancer, ovarian cancer and ductal carcinoma in situ (PMID: 10755399, 28338653, 30606148) and a suspected HBOC family (PMID: 21702907). In a large breast cancer case-control meta-analysis conducted by the BRIDGES consortium, this variant was reported in 5/60466 cases and 2/53461 unaffected controls (p-value=0.459) (PMID: 33471991; Leiden Open Variation Database DB-ID BRCA2_007696). This variant has been identified in 8/250556 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. -

not specified Uncertain:1
Mar 04, 2025
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Fanconi anemia complementation group D1 Uncertain:1
Jan 13, 2018
Illumina Laboratory Services, Illumina
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -

Medulloblastoma;C0346153:Familial cancer of breast;C1838457:Fanconi anemia complementation group D1;C2675520:Breast-ovarian cancer, familial, susceptibility to, 2;C2751641:Glioma susceptibility 3;C2931456:Familial prostate cancer;C3150546:Pancreatic cancer, susceptibility to, 2;CN033288:Wilms tumor 1 Uncertain:1
Feb 18, 2024
Fulgent Genetics, Fulgent Genetics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

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.Asn108Ser variant was not identified in the literature. The variant was identified in dbSNP (ID: rs80358568) “With uncertain significance allele”, Exome Aggregation Consortium (ExAC) database, the ClinVar database (classified as a uncertain significance variant by the Sharing Clinical Reports Project, derived from Myriad reports; BIC and Ambry Genetics) and the BIC database (2X with unknown clinical importance). This variant was identified in the Exome Aggregation Consortium (ExAC) database (released Oct 20th, 2014) in 3 of 8278 chromosomes (frequency: 0.0004) from a population of East Asian individuals, although this low number of observations and low frequency is not substantive enough to determine the prevalence of the variant in the general population and its relationship to disease. The p.Asn108Ser residue is not conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to the protein. However, this information is not predictive enough to rule out pathogenicity. The variant occurs outside of the splicing consensus sequence and one of five in-silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) predicted 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 unknown significance. -

Hereditary breast ovarian cancer syndrome Benign:1
Jan 13, 2025
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
0.091
BayesDel_addAF
Benign
-0.40
T
BayesDel_noAF
Benign
-0.49
CADD
Benign
5.7
DANN
Benign
0.65
Eigen
Benign
-0.62
Eigen_PC
Benign
-0.57
FATHMM_MKL
Benign
0.48
N
M_CAP
Uncertain
0.18
D
MetaRNN
Benign
0.083
T;T
MetaSVM
Benign
-0.89
T
PrimateAI
Benign
0.32
T
PROVEAN
Benign
-0.42
N;N
REVEL
Benign
0.17
Sift
Benign
0.055
T;T
Sift4G
Benign
0.23
T;T
Vest4
0.10
MutPred
0.15
Gain of phosphorylation at N108 (P = 0.018);Gain of phosphorylation at N108 (P = 0.018);
MVP
0.86
MPC
0.027
ClinPred
0.026
T
GERP RS
4.2
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.1
gMVP
0.084

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.

Other links and lift over

dbSNP: rs80358568; hg19: chr13-32899219; API