ENST00000380152:c.-175C>T

Variant names:

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

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The ENST00000380152.8(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 ENST00000380152.8 5_prime_UTR_premature_start_codon_gain
• Clinical Significance: Benign reviewed by expert panel B:8
• Conservation: PhyloP100: 0.117
• Publications: 6 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]

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

Our verdict: Benign. The variant received -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 VariationId is 209599.Status of the report is reviewed_by_expert_panel, 3 stars.
• 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 the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 12 AD,AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000380152.8. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	BRCA2	NM_000059.4	MANE Select	c.-175C>T		5_prime_UTR_premature_start_codon_gain	Exon 1 of 27	NP_000050.3	A0A7P0T9D7
	BRCA2	NM_000059.4	MANE Select	c.-175C>T		5_prime_UTR	Exon 1 of 27	NP_000050.3	A0A7P0T9D7
	BRCA2	NM_001406720.1		c.-175C>T		5_prime_UTR_premature_start_codon_gain	Exon 1 of 27	NP_001393649.1	A0A8V8TPZ2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	BRCA2	ENST00000380152.8	TSL:5 MANE Select	c.-175C>T		5_prime_UTR_premature_start_codon_gain	Exon 1 of 27	ENSP00000369497.3	P51587
	BRCA2	ENST00000530893.7	TSL:1	c.-540C>T		5_prime_UTR_premature_start_codon_gain	Exon 1 of 27	ENSP00000499438.2	A0A590UJI7
	BRCA2	ENST00000380152.8	TSL:5 MANE Select	c.-175C>T		5_prime_UTR	Exon 1 of 27	ENSP00000369497.3	P51587

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

African (AFR) AF: 0.00 AC: 0 AN: 2

American (AMR) AC: 0 AN: 0

Ashkenazi Jewish (ASJ) AC: 0 AN: 0

East Asian (EAS) AC: 0 AN: 0

South Asian (SAS) AC: 0 AN: 0

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 2

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 2

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 30

Other (OTH) AF: 0.00 AC: 0 AN: 6

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

African (AFR) AF: 0.0207 AC: 859 AN: 41594

American (AMR) AF: 0.00287 AC: 44 AN: 15310

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5182

South Asian (SAS) AF: 0.000829 AC: 4 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10630

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000588 AC: 4 AN: 68044

Other (OTH) AF: 0.00236 AC: 5 AN: 2116

Alfa AF: 0.00391 Hom.: 0

Bravo AF: 0.00658

ClinVar

ClinVar submissions

Significance: Benign

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
-	-	2	Breast-ovarian cancer, familial, susceptibility to, 2 (2)
-	-	2	not specified (2)
-	-	1	Fanconi anemia complementation group D1 (1)
-	-	1	Hereditary breast ovarian cancer syndrome (1)
-	-	1	Hereditary cancer-predisposing syndrome (1)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.78
CADD	Benign	8.0
DANN	Benign	0.54
PhyloP100		0.12
PromoterAI		0.070	Neutral
Mutation Taster		=300/0	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: rs55880202; hg19: chr13-32889669;