rs80359221

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 3P and 1B. PM2PP3BP6

The NM_000059.4(BRCA2):​c.9477C>A​(p.Phe3159Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000248 in 1,613,916 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 Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. F3159S) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 33)
Exomes 𝑓: 0.0000021 ( 0 hom. )

Consequence

BRCA2
NM_000059.4 missense

Scores

1
9
6

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:5B:2

Conservation

PhyloP100: 1.56
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 was made for transcript

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.833
BP6
Variant 13-32394909-C-A is Benign according to our data. Variant chr13-32394909-C-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 52847.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=4, Likely_benign=2}. Variant chr13-32394909-C-A is described in Lovd as [Likely_benign].

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
BRCA2NM_000059.4 linkc.9477C>A p.Phe3159Leu missense_variant Exon 25 of 27 ENST00000380152.8 NP_000050.3 P51587

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
BRCA2ENST00000380152.8 linkc.9477C>A p.Phe3159Leu missense_variant Exon 25 of 27 5 NM_000059.4 ENSP00000369497.3 P51587
BRCA2ENST00000530893.7 linkc.9108C>A p.Phe3036Leu missense_variant Exon 25 of 27 1 ENSP00000499438.2 A0A590UJI7
BRCA2ENST00000614259.2 linkn.*1535C>A non_coding_transcript_exon_variant Exon 24 of 26 2 ENSP00000506251.1 A0A7P0TAP7
BRCA2ENST00000614259 linkn.*1535C>A 3_prime_UTR_variant Exon 24 of 25 2 ENSP00000506251.1 A0A7P0TAP7

Frequencies

GnomAD3 genomes
AF:
0.00000657
AC:
1
AN:
152168
Hom.:
0
Cov.:
33
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:
0.0000147
Gnomad OTH
AF:
0.00
GnomAD2 exomes
AF:
0.00000398
AC:
1
AN:
251178
AF XY:
0.00
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 FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00000881
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.00000205
AC:
3
AN:
1461748
Hom.:
0
Cov.:
31
AF XY:
0.00000275
AC XY:
2
AN XY:
727180
show subpopulations
Gnomad4 AFR exome
AF:
0.00
AC:
0
AN:
33472
Gnomad4 AMR exome
AF:
0.00
AC:
0
AN:
44720
Gnomad4 ASJ exome
AF:
0.00
AC:
0
AN:
26130
Gnomad4 EAS exome
AF:
0.00
AC:
0
AN:
39682
Gnomad4 SAS exome
AF:
0.00
AC:
0
AN:
86238
Gnomad4 FIN exome
AF:
0.00
AC:
0
AN:
53408
Gnomad4 NFE exome
AF:
0.00000180
AC:
2
AN:
1111942
Gnomad4 Remaining exome
AF:
0.0000166
AC:
1
AN:
60388
Heterozygous variant carriers
0
1
1
2
2
3
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance
Exome Het
Variant carriers
0
2
4
6
8
10
<30
30-35
35-40
40-45
45-50
50-55
55-60
60-65
65-70
70-75
75-80
>80
Age
GnomAD4 genome
AF:
0.00000657
AC:
1
AN:
152168
Hom.:
0
Cov.:
33
AF XY:
0.00
AC XY:
0
AN XY:
74336
show subpopulations
Gnomad4 AFR
AF:
0.00
AC:
0
AN:
0
Gnomad4 AMR
AF:
0.00
AC:
0
AN:
0
Gnomad4 ASJ
AF:
0.00
AC:
0
AN:
0
Gnomad4 EAS
AF:
0.00
AC:
0
AN:
0
Gnomad4 SAS
AF:
0.00
AC:
0
AN:
0
Gnomad4 FIN
AF:
0.00
AC:
0
AN:
0
Gnomad4 NFE
AF:
0.0000147
AC:
0.0000146998
AN:
0.0000146998
Gnomad4 OTH
AF:
0.00
AC:
0
AN:
0
Heterozygous variant carriers
0
0
1
1
2
2
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance
Alfa
AF:
0.0000508
Hom.:
0
Bravo
AF:
0.0000113
Asia WGS
AF:
0.000577
AC:
2
AN:
3478

ClinVar

Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:5Benign:2
Revision: criteria provided, conflicting classifications
LINK: link

Submissions by phenotype

Breast-ovarian cancer, familial, susceptibility to, 2 Uncertain:1Benign:1
Feb 15, 2023
All of Us Research Program, National Institutes of Health
Significance:Likely benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

Dec 23, 2003
Breast Cancer Information Core (BIC) (BRCA2)
Significance:Uncertain significance
Review Status:no assertion criteria provided
Collection Method:clinical testing

- -

Hereditary cancer-predisposing syndrome Uncertain:1Benign:1
Jun 08, 2017
Color Diagnostics, LLC DBA Color Health
Significance:Likely benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

Jul 24, 2023
Ambry Genetics
Significance:Uncertain significance
Review Status:criteria provided, single submitter
Collection Method:clinical testing

The p.F3159L variant (also known as c.9477C>A), located in coding exon 24 of the BRCA2 gene, results from a C to A substitution at nucleotide position 9477. The phenylalanine at codon 3159 is replaced by leucine, an amino acid with highly similar properties. In a study of 1854 high-risk BR/OV cancer families in Italy, this alteration was detected in 1 family (Azzollini J et al. Eur J Intern Med, 2016 Jul;32:65-71).This amino acid position is not well conserved in available vertebrate 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. -

not specified Uncertain:1
May 08, 2025
Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Significance:Uncertain significance
Review Status:criteria provided, single submitter
Collection Method:clinical testing

Variant summary: BRCA2 c.9477C>A (p.Phe3159Leu) results in a non-conservative amino acid change located in the BRCA2, OB3 domain of the encoded protein sequence. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change. The variant allele was found at a frequency of 4e-06 in 251178 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.9477C>A has been reported in the literature in the presumed heterozygous state in individuals affected with clinical features of Hereditary Breast And Ovarian Cancer Syndrome, without strong evidence for causality (Azzollini_2016, Fanale_2021). These report(s) do not provide unequivocal conclusions about association of the variant with Hereditary Breast And Ovarian Cancer Syndrome. At least one publication reports experimental evidence evaluating an impact on protein function in vitro. These results showed no damaging effect of this variant (example, Biswas_2023). The following publications have been ascertained in the context of this evaluation (PMID: 27062684, 34178674, 19043619, 37922907). ClinVar contains an entry for this variant (Variation ID: 52847). Based on the evidence outlined above, the variant was classified as uncertain significance. -

not provided Uncertain:1
Apr 19, 2019
Quest Diagnostics Nichols Institute San Juan Capistrano
Significance:Uncertain significance
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

Hereditary breast ovarian cancer syndrome Uncertain:1
Dec 12, 2024
Labcorp Genetics (formerly Invitae), Labcorp
Significance:Uncertain significance
Review Status:criteria provided, single submitter
Collection Method:clinical testing

This sequence change replaces phenylalanine, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 3159 of the BRCA2 protein (p.Phe3159Leu). This variant is present in population databases (rs80359221, gnomAD 0.0009%). This missense change has been observed in individual(s) with breast and/or ovarian cancer (PMID: 27062684). ClinVar contains an entry for this variant (Variation ID: 52847). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) 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. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Uncertain
0.53
BayesDel_addAF
Uncertain
0.15
D
BayesDel_noAF
Uncertain
-0.020
CADD
Benign
17
DANN
Uncertain
1.0
Eigen
Uncertain
0.41
Eigen_PC
Uncertain
0.42
FATHMM_MKL
Uncertain
0.82
D
M_CAP
Benign
0.079
D
MetaRNN
Pathogenic
0.83
D;D
MetaSVM
Benign
-0.40
T
PrimateAI
Benign
0.44
T
PROVEAN
Benign
-1.3
N;N
REVEL
Uncertain
0.57
Sift
Uncertain
0.021
D;D
Sift4G
Benign
0.089
T;T
Vest4
0.62
MutPred
0.70
Loss of ubiquitination at K3161 (P = 0.1441);Loss of ubiquitination at K3161 (P = 0.1441);
MVP
0.91
MPC
0.027
ClinPred
0.69
D
GERP RS
5.0
gMVP
0.28
Mutation Taster
=76/23
polymorphism

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: rs80359221; hg19: chr13-32969046; API