chr13-32338520-T-G

Variant names:

• chr13-32338520-T-G
• rs1409088355
• NM_000059.4:c.4165T>G

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 0P and 2B. BP4_Moderate

The NM_000059.4(BRCA2):​c.4165T>G​(p.Phe1389Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000561 in 1,603,280 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign 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. F1389L) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0000055 (0 hom.)
• Consequence: BRCA2 NM_000059.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:8 B:1
• Conservation: PhyloP100: 3.13
• Publications: 8 publications found

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 Gene-Disease associations (from GenCC):

• breast-ovarian cancer, familial, susceptibility to, 2

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Ambry Genetics, Genomics England PanelApp, Labcorp Genetics (formerly Invitae), ClinGen
• Fanconi anemia complementation group D1

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics, ClinGen, G2P
• pancreatic cancer, susceptibility to, 2

  Inheritance: AD Classification: STRONG Submitted by: Genomics England PanelApp
• sarcoma

  Inheritance: AD Classification: MODERATE Submitted by: Genomics England PanelApp
• hereditary breast ovarian cancer syndrome

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• Fanconi anemia

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• medulloblastoma

  Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics

ACMG classification

Our verdict: Likely_benign. The variant received -2 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.19213983).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
BRCA2	NM_000059.4	c.4165T>G	p.Phe1389Val	missense_variant	Exon 11 of 27	ENST00000380152.8	NP_000050.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
BRCA2	ENST00000380152.8	c.4165T>G	p.Phe1389Val	missense_variant	Exon 11 of 27	5	NM_000059.4	ENSP00000369497.3
BRCA2	ENST00000530893.7	c.3796T>G	p.Phe1266Val	missense_variant	Exon 11 of 27	1		ENSP00000499438.2
BRCA2	ENST00000614259.2	n.4165T>G		non_coding_transcript_exon_variant	Exon 10 of 26	2		ENSP00000506251.1

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152196 Hom.: 0 Cov.: 33

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: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00000421 AC: 1 AN: 237332 AF XY: 0.00000779

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: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000551 AC: 8 AN: 1451084 Hom.: 0 Cov.: 35 AF XY: 0.00000277 AC XY: 2 AN XY: 721206

African (AFR) AF: 0.00 AC: 0 AN: 32852

American (AMR) AF: 0.00 AC: 0 AN: 41858

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25650

East Asian (EAS) AF: 0.00 AC: 0 AN: 39604

South Asian (SAS) AF: 0.0000843 AC: 7 AN: 83086

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53248

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5710

European-Non Finnish (NFE) AF: 9.02e-7 AC: 1 AN: 1109132

Other (OTH) AF: 0.00 AC: 0 AN: 59944

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152196 Hom.: 0 Cov.: 33 AF XY: 0.0000134 AC XY: 1 AN XY: 74366

African (AFR) AF: 0.00 AC: 0 AN: 41448

American (AMR) AF: 0.00 AC: 0 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5198

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10626

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68018

Other (OTH) AF: 0.00 AC: 0 AN: 2094

Alfa AF: 0.0000330 Hom.: 0

Bravo AF: 0.0000113

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:8 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Hereditary cancer-predisposing syndrome Uncertain:2 Benign:1

Jun 19, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.F1389V variant (also known as c.4165T>G), located in coding exon 10 of the BRCA2 gene, results from a T to G substitution at nucleotide position 4165. The phenylalanine at codon 1389 is replaced by valine, an amino acid with highly similar properties. This variant was observed in a study of 1010 unrelated Indian patients with breast and/or ovarian cancer (Singh J et al. Breast Cancer Res Treat, 2018 Jul;170:189-196). This amino acid position is poorly 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. -

Mar 23, 2023

University of Washington Department of Laboratory Medicine, University of Washington

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: curation

Missense variant in a coldspot region where missense variants are very unlikely to be pathogenic (PMID:31911673). -

Jan 25, 2023

Color Diagnostics, LLC DBA Color Health

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This missense variant replaces phenylalanine with valine at codon 1389 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 three individuals affected with breast or ovarian cancer (PMID: 29470806, DOI: 10.4103/bbrj.bbrj_206_21). This variant has been identified in 1/237332 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. -

Breast-ovarian cancer, familial, susceptibility to, 2 Uncertain:2

May 04, 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 phenylalanine with valine at codon 1389 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 three individuals affected with breast or ovarian cancer (PMID: 29470806, DOI: 10.4103/bbrj.bbrj_206_21). This variant has been identified in 1/237332 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. -

Feb 14, 2023

Neuberg Centre For Genomic Medicine, NCGM

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The missense c.4165T>G(p.Phe1389Val) variant in BRCA2 gene has been reported previously in individual affected with BRCA2associated disorders (Reeba Mary Issac, et. al., 2022). The variant is reported with an allele frequency of 0.0004% in the gnomADexomes database and is novel (not in any individuals) in 1000 Genomes database. This variant has been reported to the ClinVardatabase as Uncertain significance (multiple submission). The amino acid change p.Phe1389Val in BRCA2 is predicted asconserved by GERP++ and PhyloP across 100 vertebrates. The amino acid Phe at position 1389 is changed to a Val changing proteinsequence and it might alter its composition and physico-chemical properties. For these reasons, this variant has been classifiedas Variant of Uncertain Significance (VUS). -

not provided Uncertain:2

May 08, 2020

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The BRCA2 c.4165T>G; p.Phe1389Val variant (rs1409088355) is reported in the literature in several individuals affected with breast and/or ovarian cancer (Singh 2018). This variant is found on a single chromosome in the Genome Aggregation Database (1/237332 alleles), indicating it is not a common polymorphism. The phenylalanine at codon 1389 is weakly conserved, and computational analyses (SIFT: damaging, PolyPhen-2: benign) predict conflicting effects of this variant on protein structure/function. However, given the lack of clinical and functional data, the significance of the p.Phe1389Val variant is uncertain at this time. References: Singh J et al. Screening of over 1000 Indian patients with breast and/or ovarian cancer with a multi-gene panel: prevalence of BRCA1/2 and non-BRCA mutations. Breast Cancer Res Treat. 2018 Jul;170(1):189-196. -

Dec 23, 2022

Quest Diagnostics Nichols Institute San Juan Capistrano

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The frequency of this variant in the general population, 0.0000042 (1/237332 chromosomes, http://gnomad.broadinstitute.org), is uninformative in assessment of its pathogenicity. In the published literature, the variant has been reported in an individual affected with breast and/or ovarian cancer (PMID: 29470806 (2018)). 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. -

not specified Uncertain:1

Jun 04, 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.4165T>G (p.Phe1389Val) results in a non-conservative amino acid change located in the BRCA2 repeat region (IPR002093) 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 4.2e-06 in 237332 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.4165T>G has been observed in individual(s) affected with Hereditary Breast And Ovarian Cancer Syndrome (Singh_2018). These report(s) do not provide unequivocal conclusions about association of the variant with Hereditary Breast And Ovarian Cancer Syndrome. 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: 28526081, 29470806). ClinVar contains an entry for this variant (Variation ID: 462329). Based on the evidence outlined above, the variant was classified as uncertain significance. -

Hereditary breast ovarian cancer syndrome Uncertain:1

Jan 18, 2022

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 valine, which is neutral and non-polar, at codon 1389 of the BRCA2 protein (p.Phe1389Val). This variant is present in population databases (no rsID available, gnomAD 0.004%). This missense change has been observed in individual(s) with breast and/or ovarian cancer (PMID: 29470806). ClinVar contains an entry for this variant (Variation ID: 462329). 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. 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	0.10
BayesDel_addAF	Benign	-0.14	T
BayesDel_noAF	Benign	-0.33
CADD	Benign	23
DANN	Uncertain	0.98
Eigen	Benign	-0.17
Eigen_PC	Benign	0.030
FATHMM_MKL	Uncertain	0.94	D
M_CAP	Uncertain	0.22	D
MetaRNN	Benign	0.19	T;T
MetaSVM	Benign	-0.84	T
PhyloP100		3.1
PrimateAI	Benign	0.36	T
PROVEAN	Benign	0.38	N;N
REVEL	Benign	0.21
Sift	Uncertain	0.0020	D;D
Sift4G	Uncertain	0.035	D;D
Vest4		0.32
MVP		0.85
MPC		0.024
ClinPred		0.34	T
GERP RS		6.0
gMVP		0.28
Mutation Taster		=90/10	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

Other links and lift over

dbSNP: rs1409088355; hg19: chr13-32912657; COSMIC: COSV66456499;