NM_000059.4:c.-175C>T

Variant names:

• chr13-32315532-C-T
• rs55880202
• NM_000059.4:c.-175C>T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_000059.4(BRCA2):​c.-175C>T variant causes a 5 prime UTR premature start codon gain change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00601 in 152,382 control chromosomes in the GnomAD database, including 12 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★★).

• Frequency:
  • Genomes: 𝑓 0.0060 (12 hom., cov: 33)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: BRCA2 NM_000059.4 5_prime_UTR_premature_start_codon_gain
• Clinical Significance: Benign reviewed by expert panel B:8
• Conservation: PhyloP100: 0.117

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]

ZAR1L (HGNC:37116): (zygote arrest 1 like) This gene encodes a member of the ZAR1 family that is predominantly expressed in oocytes and early embryos. The protein may function as an RNA regulator in early embryos. [provided by RefSeq, Apr 2010]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.78).
• BP6: Variant 13-32315532-C-T is Benign according to our data. Variant chr13-32315532-C-T is described in ClinVar as [Benign]. Clinvar id is 209599.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr13-32315532-C-T is described in Lovd as [Benign].
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00601 (916/152382) while in subpopulation AFR AF= 0.0207 (859/41594). AF 95% confidence interval is 0.0195. There are 12 homozygotes in gnomad4. There are 450 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 12 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
BRCA2	NM_000059.4	c.-175C>T		5_prime_UTR_premature_start_codon_gain_variant	Exon 1 of 27	ENST00000380152.8	NP_000050.3
BRCA2	NM_000059.4	c.-175C>T		5_prime_UTR_variant	Exon 1 of 27	ENST00000380152.8	NP_000050.3
ZAR1L	NM_001136571.2	c.-607G>A		upstream_gene_variant		ENST00000533490.7	NP_001130043.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
BRCA2	ENST00000380152	c.-175C>T		5_prime_UTR_premature_start_codon_gain_variant	Exon 1 of 27	5	NM_000059.4	ENSP00000369497.3
BRCA2	ENST00000530893	c.-540C>T		5_prime_UTR_premature_start_codon_gain_variant	Exon 1 of 27	1		ENSP00000499438.2
BRCA2	ENST00000380152	c.-175C>T		5_prime_UTR_variant	Exon 1 of 27	5	NM_000059.4	ENSP00000369497.3
BRCA2	ENST00000530893	c.-540C>T		5_prime_UTR_variant	Exon 1 of 27	1		ENSP00000499438.2
ZAR1L	ENST00000533490.7	c.-607G>A		upstream_gene_variant		5	NM_001136571.2	ENSP00000437289.2

Frequencies

GnomAD3 genomes AF: 0.00600 AC: 914 AN: 152264 Hom.: 12 Cov.: 33

Gnomad AFR AF: 0.0207

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00288

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000828

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000588

Gnomad OTH AF: 0.00239

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 42 Hom.: 0 Cov.: 0 AF XY: 0.00 AC XY: 0 AN XY: 30

Gnomad4 AFR exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.00601 AC: 916 AN: 152382 Hom.: 12 Cov.: 33 AF XY: 0.00604 AC XY: 450 AN XY: 74508

Gnomad4 AFR AF: 0.0207

Gnomad4 AMR AF: 0.00287

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000829

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000588

Gnomad4 OTH AF: 0.00236

Alfa AF: 0.00343 Hom.: 0

Bravo AF: 0.00658

ClinVar

Significance: Benign

Submissions summary: Benign:8

Revision: reviewed by expert panel

Submissions by phenotype

not specified Benign:2

Nov 01, 2017

GeneKor MSA

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

May 02, 2017

Genetic Services Laboratory, University of Chicago

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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

Jan 12, 2015

Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA)

Significance: Benign

Review Status: reviewed by expert panel

Collection Method: curation

Class 1 not pathogenic based on frequency >1% in an outbred sampleset. Frequency 0.03659 (African), derived from 1000 genomes (2012-04-30). -

Feb 09, 2018

Illumina Laboratory Services, Illumina

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

Fanconi anemia complementation group D1 Benign:1

Feb 09, 2018

Illumina Laboratory Services, Illumina

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

not provided Benign:1

Jun 18, 2018

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Hereditary cancer-predisposing syndrome Benign:1

Mar 28, 2020

Sema4, Sema4

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: curation

- -

Hereditary breast ovarian cancer syndrome Benign:1

Oct 14, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.78
CADD	Benign	8.0
DANN	Benign	0.54

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: rs55880202; hg19: chr13-32889669;