chr13-32380124-G-C

Variant names:

• chr13-32380124-G-C
• rs55933907
• NM_000059.4:c.9235G>C

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 4P and 2B. PM1 PM2 BP6_Moderate

The NM_000059.4(BRCA2):​c.9235G>C​(p.Val3079Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Likely benign (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V3079F) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: BRCA2 NM_000059.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:1
• Conservation: PhyloP100: -0.168
• Publications: 0 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 11 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 14 benign, 26 uncertain in NM_000059.4
• PM2: Very rare variant in population databases, with high coverage
• BP6: Variant 13-32380124-G-C is Benign according to our data. Variant chr13-32380124-G-C is described in ClinVar as Likely_benign. ClinVar VariationId is 2566026.Status of the report is criteria_provided_single_submitter, 1 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000059.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	BRCA2	NM_000059.4	MANE Select	c.9235G>C	p.Val3079Leu	missense	Exon 24 of 27	NP_000050.3
	BRCA2	NM_001432077.1		c.9235G>C	p.Val3079Leu	missense	Exon 24 of 27	NP_001419006.1
	BRCA2	NM_001406720.1		c.9184G>C	p.Val3062Leu	missense	Exon 24 of 27	NP_001393649.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	BRCA2	ENST00000380152.8	TSL:5 MANE Select	c.9235G>C	p.Val3079Leu	missense	Exon 24 of 27	ENSP00000369497.3
	BRCA2	ENST00000544455.6	TSL:1	c.9235G>C	p.Val3079Leu	missense	Exon 24 of 27	ENSP00000439902.1
	BRCA2	ENST00000530893.7	TSL:1	c.8866G>C	p.Val2956Leu	missense	Exon 24 of 27	ENSP00000499438.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:1

Jan 24, 2024

Genetic Services Laboratory, University of Chicago

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

DNA sequence analysis of the BRCA2 gene demonstrated a sequence change, c.9235G>C, in exon 24 that results in an amino acid change, p.Val3079Leu. This sequence change does not appear to have been previously described in individuals with BRCA2-related disorders and has also not been described in population databases such as ExAC and gnomAD. The p.Val3079Leu change affects a moderately conserved amino acid residue located in a domain of the BRCA2 protein that is known to be functional. In-silico pathogenicity prediction tools (SIFT, PolyPhen2, Align GVGD, REVEL) provide contradictory results for the p.Val3079Leu substitution. Due to insufficient evidences and the lack of functional studies, the clinical significance of the p.Val3079Leu change remains unknown at this time.

Hereditary cancer-predisposing syndrome Benign:1

May 15, 2025

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.

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.29
BayesDel_addAF	Uncertain	0.12	D
BayesDel_noAF	Uncertain	-0.070
CADD	Benign	14
DANN	Uncertain	1.0
Eigen	Benign	0.17
Eigen_PC	Benign	0.081
FATHMM_MKL	Benign	0.36	N
M_CAP	Uncertain	0.11	D
MetaRNN	Uncertain	0.61	D
MetaSVM	Uncertain	0.17	D
PhyloP100		-0.17
PrimateAI	Benign	0.35	T
PROVEAN	Benign	-0.69	N
REVEL	Uncertain	0.55
Sift	Uncertain	0.0060	D
Sift4G	Uncertain	0.033	D
Vest4		0.42
MutPred		0.64		Loss of sheet (P = 0.0228)
MVP		0.91
MPC		0.071
ClinPred		0.74	D
GERP RS		3.4
gMVP		0.32
Mutation Taster		=93/7	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: rs55933907; hg19: chr13-32954261;