17-43124135-CATATAT-CATATATAT

Variant names:

• chr17-43124135-C-CAT
• rs273898667
• NM_007294.4:c.-19-22_-19-21dupAT

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP6_Very_Strong

The NM_001407593.1(BRCA1):​c.-41_-40dupAT variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000303 in 1,291,020 control chromosomes in the GnomAD database, including 1 homozygotes. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.00065 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00026 (1 hom.)
• Consequence: BRCA1 NM_001407593.1 5_prime_UTR
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 0.118

Genes affected

BRCA1 (HGNC:1100): (BRCA1 DNA repair associated) This gene encodes a 190 kD nuclear phosphoprotein that plays a role in maintaining genomic stability, and it also acts as a tumor suppressor. The BRCA1 gene contains 22 exons spanning about 110 kb of DNA. The encoded protein combines with other tumor suppressors, DNA damage sensors, and signal transducers to form a large multi-subunit protein complex known as the BRCA1-associated genome surveillance complex (BASC). This gene product associates with RNA polymerase II, and through the C-terminal domain, also interacts with histone deacetylase complexes. This protein thus plays a role in transcription, DNA repair of double-stranded breaks, and recombination. Mutations in this gene are responsible for approximately 40% of inherited breast cancers and more than 80% of inherited breast and ovarian cancers. Alternative splicing plays a role in modulating the subcellular localization and physiological function of this gene. Many alternatively spliced transcript variants, some of which are disease-associated mutations, have been described for this gene, but the full-length natures of only some of these variants has been described. A related pseudogene, which is also located on chromosome 17, has been identified. [provided by RefSeq, May 2020]

ACMG classification

Verdict is Benign. Variant got -8 ACMG points.

• BP6: Variant 17-43124135-C-CAT is Benign according to our data. Variant chr17-43124135-C-CAT is described in ClinVar as [Likely_benign]. Clinvar id is 225725.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
BRCA1	NM_007294.4	c.-19-22_-19-21dupAT		intron_variant	Intron 1 of 22	ENST00000357654.9	NP_009225.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
BRCA1	ENST00000357654.9	c.-19-22_-19-21dupAT		intron_variant	Intron 1 of 22	1	NM_007294.4	ENSP00000350283.3

Frequencies

GnomAD3 genomes AF: 0.000646 AC: 98 AN: 151788 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00150

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000985

Gnomad ASJ AF: 0.00260

Gnomad EAS AF: 0.000385

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000147

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000439 AC: 94 AN: 213924 Hom.: 0 AF XY: 0.000386 AC XY: 45 AN XY: 116510

Gnomad AFR exome AF: 0.00180

Gnomad AMR exome AF: 0.000629

Gnomad ASJ exome AF: 0.00222

Gnomad EAS exome AF: 0.000331

Gnomad SAS exome AF: 0.000146

Gnomad FIN exome AF: 0.0000519

Gnomad NFE exome AF: 0.000194

Gnomad OTH exome AF: 0.000369

GnomAD4 exome AF: 0.000256 AC: 292 AN: 1139114 Hom.: 1 Cov.: 16 AF XY: 0.000255 AC XY: 148 AN XY: 580572

Gnomad4 AFR exome AF: 0.00108

Gnomad4 AMR exome AF: 0.000793

Gnomad4 ASJ exome AF: 0.00208

Gnomad4 EAS exome AF: 0.000249

Gnomad4 SAS exome AF: 0.000180

Gnomad4 FIN exome AF: 0.0000578

Gnomad4 NFE exome AF: 0.000161

Gnomad4 OTH exome AF: 0.000427

GnomAD4 genome AF: 0.000652 AC: 99 AN: 151906 Hom.: 0 Cov.: 32 AF XY: 0.000620 AC XY: 46 AN XY: 74250

Gnomad4 AFR AF: 0.00152

Gnomad4 AMR AF: 0.000984

Gnomad4 ASJ AF: 0.00260

Gnomad4 EAS AF: 0.000386

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000147

Gnomad4 OTH AF: 0.00

Bravo AF: 0.000740

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

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

Apr 21, 2016

Michigan Medical Genetics Laboratories, University of Michigan

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Nov 14, 1997

Breast Cancer Information Core (BIC) (BRCA1)

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Hereditary cancer-predisposing syndrome Benign:1

May 20, 2021

Sema4, Sema4

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: curation

- -

Hereditary breast ovarian cancer syndrome Benign:1

Nov 29, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs273898667; hg19: chr17-41276152;