chr13-32379922-C-T

Position:

• chr13-32379922-C-T

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 2P and 12B. PM2 BP4_Strong BP6_Very_Strong

The NM_000059.4(BRCA2):​c.9117+9C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000205 in 1,460,842 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: BRCA2 NM_000059.4 intron
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts U:1 B:5
• Conservation: PhyloP100: 0.157

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 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -10 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.8).
• BP6: Variant 13-32379922-C-T is Benign according to our data. Variant chr13-32379922-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 52757.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr13-32379922-C-T is described in Lovd as [Benign].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
BRCA2	NM_000059.4	c.9117+9C>T		intron_variant		ENST00000380152.8	NP_000050.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
BRCA2	ENST00000380152.8	c.9117+9C>T		intron_variant		5	NM_000059.4	ENSP00000369497.3
BRCA2	ENST00000530893.7	c.8748+9C>T		intron_variant		1		ENSP00000499438.2
BRCA2	ENST00000614259.2	n.*1175+9C>T		intron_variant		2		ENSP00000506251.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000403 AC: 1 AN: 248092 Hom.: 0 AF XY: 0.00000745 AC XY: 1 AN XY: 134282

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 SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000897

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000205 AC: 3 AN: 1460842 Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1 AN XY: 726680

Gnomad4 AFR exome AF: 0.00

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: 0.00000270

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely benign

Submissions summary: Uncertain:1 Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

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

Uncertain significance, no assertion criteria provided	clinical testing	Breast Cancer Information Core (BIC) (BRCA2)	Feb 20, 2004	- -
Likely benign, criteria provided, single submitter	clinical testing	Counsyl	Jan 27, 2016	- -

not specified Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Feb 08, 2017	- -
Likely benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jan 06, 2023	Variant summary: BRCA2 c.9117+9C>T alters a non-conserved nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. 4/4 computational tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 4e-06 in 248092 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 conclusive evidence regarding the occurrence of c.9117+9C>T in individuals affected with Hereditary Breast And Ovarian Cancer Syndrome and no experimental evidence demonstrating its impact on protein function have been reported. At-least one co-occurrence with another pathogenic variant(s) have been reported in the BIC database (BRCA1 c.66_67delAG, p.Leu22_Glu23LeuValfs), providing supporting evidence for a benign role. Four 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 likely benign. Based on the evidence outlined above, the variant was classified as likely benign. -

Hereditary cancer-predisposing syndrome Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Color Diagnostics, LLC DBA Color Health

Jun 13, 2018

- -

Hereditary breast ovarian cancer syndrome Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Oct 16, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.80
CADD	Benign	4.2
DANN	Benign	0.68

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

Other links and lift over

dbSNP: rs81002869; hg19: chr13-32954059;