chr17-43125979-T-C

Position:

• chr17-43125979-T-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001408458.1(BRCA1):​c.-61-10200A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0497 in 137,476 control chromosomes in the GnomAD database, including 208 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★★).

• Frequency: Genomes: 𝑓 0.050 (208 hom., cov: 32)
• Consequence: BRCA1 NM_001408458.1 intron
• Clinical Significance: Benign reviewed by expert panel B:1
• Conservation: PhyloP100: 1.08

Genes affected

NBR2 (HGNC:):

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.8).
• BP6: Variant 17-43125979-T-C is Benign according to our data. Variant chr17-43125979-T-C is described in ClinVar as [Benign]. Clinvar id is 209581.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr17-43125979-T-C is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0699 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
BRCA1	NM_001408458.1	c.-61-10200A>G		intron_variant			NP_001395387.1
NBR2	NR_003108.2	n.214+209T>C		intron_variant
NBR2	NR_138145.1	n.214+209T>C		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NBR2	ENST00000356906.7	n.131+209T>C		intron_variant		1
BRCA1	ENST00000634433.2	c.-19-1864A>G		intron_variant		5		ENSP00000489431.2
NBR2	ENST00000460115.5	n.161+209T>C		intron_variant		2

Frequencies

GnomAD3 genomes AF: 0.0497 AC: 6828 AN: 137362 Hom.: 207 Cov.: 32

Gnomad AFR AF: 0.0124

Gnomad AMI AF: 0.0180

Gnomad AMR AF: 0.0428

Gnomad ASJ AF: 0.0896

Gnomad EAS AF: 0.000663

Gnomad SAS AF: 0.0172

Gnomad FIN AF: 0.0981

Gnomad MID AF: 0.0420

Gnomad NFE AF: 0.0716

Gnomad OTH AF: 0.0600

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.0497 AC: 6829 AN: 137476 Hom.: 208 Cov.: 32 AF XY: 0.0495 AC XY: 3305 AN XY: 66744

Gnomad4 AFR AF: 0.0124

Gnomad4 AMR AF: 0.0427

Gnomad4 ASJ AF: 0.0896

Gnomad4 EAS AF: 0.000663

Gnomad4 SAS AF: 0.0169

Gnomad4 FIN AF: 0.0981

Gnomad4 NFE AF: 0.0717

Gnomad4 OTH AF: 0.0594

Alfa AF: 0.0597 Hom.: 34

Bravo AF: 0.0406

Asia WGS AF: 0.00550 AC: 19 AN: 3470

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: reviewed by expert panel

Submissions by phenotype

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

Benign, reviewed by expert panel

curation

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

Jan 12, 2015

Class 1 not pathogenic based on frequency >1% in an outbred sampleset. Frequency 0.06 (European), derived from 1000 genomes (2012-04-30). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.80
CADD	Benign	14
DANN	Benign	0.51

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs3092986; hg19: chr17-41277996;