13-32380049-C-T

Variant names:

• chr13-32380049-C-T
• rs786204070
• NM_000059.4:c.9160C>T

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 4P and 2B. PM1 PM2 BP4_Moderate

The NM_000059.4(BRCA2):​c.9160C>T​(p.Pro3054Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 14/20 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. P3054L) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: BRCA2 NM_000059.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:5 B:1
• Conservation: PhyloP100: 0.341
• 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: Uncertain_significance. The variant received 2 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 17 benign, 25 uncertain in NM_000059.4
• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.07268062).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
BRCA2	NM_000059.4	c.9160C>T	p.Pro3054Ser	missense_variant	Exon 24 of 27	ENST00000380152.8	NP_000050.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
BRCA2	ENST00000380152.8	c.9160C>T	p.Pro3054Ser	missense_variant	Exon 24 of 27	5	NM_000059.4	ENSP00000369497.3
BRCA2	ENST00000530893.7	c.8791C>T	p.Pro2931Ser	missense_variant	Exon 24 of 27	1		ENSP00000499438.2
BRCA2	ENST00000614259.2	n.*1218C>T		non_coding_transcript_exon_variant	Exon 23 of 26	2		ENSP00000506251.1
BRCA2	ENST00000614259.2	n.*1218C>T		3_prime_UTR_variant	Exon 23 of 26	2		ENSP00000506251.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:5 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Hereditary cancer-predisposing syndrome Uncertain:1 Benign:1

Jan 11, 2022

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. -

Dec 21, 2022

Color Diagnostics, LLC DBA Color Health

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This missense variant replaces proline with serine at codon 3054 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). A functional study has reported that this variant does not impact BRCA2 function as assayed by response to PARP inhibitors (PMID: 32444794). This variant has not been reported in individuals affected with BRCA2-related disorders in the literature. This variant has not been identified 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

Sep 11, 2021

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.9160C>T (p.Pro3054Ser) results in a non-conservative amino acid change located in the BRCA2, OB3 domain (IPR015188) of the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant was absent in 251260 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.9160C>T in individuals affected with Hereditary Breast And Ovarian Cancer Syndrome has been reported. At least one publication reports experimental evidence evaluating an impact on protein function (Ikegami_2020). Tumors with pathogenic variants within BRCA and defective HDR have been shown to be particularly sensitive to platinum-based chemotherapies and poly (ADP-ribose) polymerase (PARP) inhibitors, the efficacy of which is mediated through synthetic lethality in cancer cells with BRCA loss-of function. These results showed no damaging effect of this variant on homology directed repair (HDR capacity) based on a high throughput cell based viability assay (MANO-B method) to evaluate drug sensitivity of the BRCA2 variants treated with PARP inhibitors (olaparib, niraparib, rucaparib and carboplatin) at various concentrations. Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance. -

not provided Uncertain:1

Aug 26, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The BRCA2 c.9160C>T; p.Pro3054Ser variant (rs786204070), to our knowledge, is not reported in the medical literature but is reported in ClinVar (Variation ID: 188105). This variant is absent from the Genome Aggregation Database (v2.1.1), indicating it is not a common polymorphism. This variant is located within the BRCA2 DNA binding domain, but computational analyses predict that this variant is neutral (BayesDel). Due to limited information, the clinical significance of this variant is uncertain at this time. -

Familial cancer of breast Uncertain:1

Nov 22, 2023

Baylor Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Hereditary breast ovarian cancer syndrome Uncertain:1

Jan 19, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces proline, which is neutral and non-polar, with serine, which is neutral and polar, at codon 3054 of the BRCA2 protein (p.Pro3054Ser). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with BRCA2-related conditions. ClinVar contains an entry for this variant (Variation ID: 188105). 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	Benign	0.14
BayesDel_addAF	Benign	0.0062	T
BayesDel_noAF	Benign	-0.23
CADD	Benign	12
DANN	Benign	0.76
Eigen	Benign	-1.0
Eigen_PC	Benign	-0.98
FATHMM_MKL	Benign	0.036	N
M_CAP	Benign	0.052	D
MetaRNN	Benign	0.073	T;T
MetaSVM	Benign	-0.90	T
PhyloP100		0.34
PrimateAI	Benign	0.23	T
PROVEAN	Benign	-1.1	N;N
REVEL	Uncertain	0.33
Sift	Benign	0.45	T;T
Sift4G	Benign	0.32	T;T
Vest4		0.17
MutPred		0.37		Gain of phosphorylation at P3054 (P = 0.0587);Gain of phosphorylation at P3054 (P = 0.0587);
MVP		0.80
MPC		0.022
ClinPred		0.043	T
GERP RS		-0.81
gMVP		0.22
Mutation Taster		=85/15	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: rs786204070; hg19: chr13-32954186;