13-32379812-T-G

Variant names:

• chr13-32379812-T-G
• rs397507416
• NM_000059.4:c.9016T>G

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM2 PP3_Moderate PP5

The NM_000059.4(BRCA2):​c.9016T>G​(p.Tyr3006Asp) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000685 in 1,460,052 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).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: BRCA2 NM_000059.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:5 U:3
• Conservation: PhyloP100: 7.22

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 5 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.885
• PP5: Variant 13-32379812-T-G is Pathogenic according to our data. Variant chr13-32379812-T-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 38202.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=5, Uncertain_significance=3}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
BRCA2	NM_000059.4	c.9016T>G	p.Tyr3006Asp	missense_variant	Exon 23 of 27	ENST00000380152.8	NP_000050.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
BRCA2	ENST00000380152.8	c.9016T>G	p.Tyr3006Asp	missense_variant	Exon 23 of 27	5	NM_000059.4	ENSP00000369497.3
BRCA2	ENST00000530893.7	c.8647T>G	p.Tyr2883Asp	missense_variant	Exon 23 of 27	1		ENSP00000499438.2
BRCA2	ENST00000614259.2	n.*1074T>G		non_coding_transcript_exon_variant	Exon 22 of 26	2		ENSP00000506251.1
BRCA2	ENST00000614259	n.*1074T>G		3_prime_UTR_variant	Exon 22 of 25	2		ENSP00000506251.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.85e-7 AC: 1 AN: 1460052 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 726464

Gnomad4 AFR exome AF: 0.0000299

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: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:5 Uncertain:3

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Pathogenic:2

Mar 18, 2025

GeneDx

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Published functional studies demonstrate a damaging effect: defective homology-directed repair activity and sensitivity to PARP inhibitors (PMID: 32377563, 32444794, 33609447, 35665744, 35736817); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Also known as 9244T>G; This variant is associated with the following publications: (PMID: 25722345, 32377563, 35736817, 33609447, 32444794, 29884841, 35665744, 28569743, 31911673, 31853058, 12228710) -

Jan 24, 2024

Quest Diagnostics Nichols Institute San Juan Capistrano

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The BRCA2 c.9016T>G (p.Tyr3006Asp) variant has been reported in the published literature in an individual who underwent multigene panel testing (PMID: 31853058 (2020)), and has been reported in an individual with breast cancer (GeneDx, personal communications). Experimental studies have demonstrated this variant is damaging to BRCA2 protein function (PMID: 32444794 (2020), 33609447 (2021), 35736817 (2022)). This variant has not been reported in large, multi-ethnic general populations (Genome Aggregation Database, http://gnomad.broadinstitute.org). 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 damaging. Based on the available information, this variant is classified as likely pathogenic. -

Hereditary breast ovarian cancer syndrome Pathogenic:2

Aug 27, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces tyrosine, which is neutral and polar, with aspartic acid, which is acidic and polar, at codon 3006 of the BRCA2 protein (p.Tyr3006Asp). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with prostate cancer and breast cancer (internal data). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 38202). Invitae Evidence Modeling incorporating data from in vitro experimental studies (PMID: 33609447) indicates that this missense variant is expected to disrupt BRCA2 function with a positive predictive value of 95%. Experimental studies have shown that this missense change affects BRCA2 function (PMID: 32444794, 33609447). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. -

Jun 27, 2024

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: BRCA2 c.9016T>G (p.Tyr3006Asp) results in a non-conservative amino acid change located in the BRCA2, OB2 domain (IPR048262) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 250700 control chromosomes. c.9016T>G has been reported in the literature in a setting of multi-gene panel testing in at least one individual with personal or family history of cancer (e.g. Li_2020). This report does not provide unequivocal conclusions about association of the variant with Hereditary Breast And Ovarian Cancer Syndrome. At least two publications report experimental evidence evaluating an impact on protein function showing moderate disruption of BRCA2 function in HDR assay (e.g. Richardson_2021) and sensitivity to PARP inhibitors in vitro (e.g. Yamazawa_2023). ClinVar contains an entry for this variant (Variation ID: 38202). Based on the evidence outlined above, the variant was classified as likely pathogenic. -

Hereditary cancer-predisposing syndrome Pathogenic:1 Uncertain:1

May 06, 2024

Ambry Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.Y3006D variant (also known as c.9016T>G), located in coding exon 22 of the BRCA2 gene, results from a T to G substitution at nucleotide position 9016. The tyrosine at codon 3006 is replaced by aspartic acid, an amino acid with highly dissimilar properties. This alteration is non functional in multiple assays including a homology-directed, DNA repair assay and multiple drug sensitivity assays (Richardson ME et al. Am J Hum Genet, 2021 03;108:458-468; Ikegami M et al. Nat Commun, 2020 05;11:2573). Based on internal structural analysis, this variant is anticipated to result in a significant decrease in structural stability (Ambry internal data; Yang H et al. Science, 2002 Sep;297:1837-48). This amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the majority of available evidence to date, this variant is likely to be pathogenic. -

Jan 24, 2019

Color Diagnostics, LLC DBA Color Health

Significance: Uncertain significance

Review Status: flagged submission

Collection Method: clinical testing

- -

Breast-ovarian cancer, familial, susceptibility to, 2 Uncertain:1

Oct 16, 2006

Sharing Clinical Reports Project (SCRP)

Significance: Uncertain significance

Review Status: flagged submission

Collection Method: clinical testing

- -

Familial cancer of breast Uncertain:1

Mar 21, 2024

Baylor Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.96
BayesDel_addAF	Pathogenic	0.40	D
BayesDel_noAF	Pathogenic	0.33
CADD	Pathogenic	27
DANN	Uncertain	0.99
Eigen	Pathogenic	0.85
Eigen_PC	Pathogenic	0.81
FATHMM_MKL	Pathogenic	0.99	D
M_CAP	Pathogenic	0.32	D
MetaRNN	Pathogenic	0.88	D;D
MetaSVM	Uncertain	0.48	D
PrimateAI	Uncertain	0.52	T
PROVEAN	Uncertain	-2.6	D;D
REVEL	Pathogenic	0.77
Sift	Pathogenic	0.0	D;D
Sift4G	Pathogenic	0.0	D;D
Vest4		0.79
MutPred		0.70		Loss of sheet (P = 0.0084);Loss of sheet (P = 0.0084);
MVP		0.94
MPC		0.19
ClinPred		0.99	D
GERP RS		5.7
gMVP		0.86

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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

Other links and lift over

dbSNP: rs397507416; hg19: chr13-32953949;