17-43124230-A-G

Variant names:

• chr17-43124230-A-G
• rs3765640
• NM_007294.4:c.-19-115T>C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_007294.4(BRCA1):​c.-19-115T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.341 in 672,880 control chromosomes in the GnomAD database, including 40,431 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★★).

• Frequency:
  • Genomes: 𝑓 0.32 (7949 hom., cov: 32)
  • Exomes 𝑓: 0.35 (32482 hom.)
• Consequence: BRCA1 NM_007294.4 intron
• Clinical Significance: Benign reviewed by expert panel U:1 B:6
• Conservation: PhyloP100: -0.112
• Publications: 32 publications found

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]

BRCA1 Gene-Disease associations (from GenCC):

• breast-ovarian cancer, familial, susceptibility to, 1

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Ambry Genetics, ClinGen, Labcorp Genetics (formerly Invitae), Genomics England PanelApp
• Fanconi anemia, complementation group S

  Inheritance: AR Classification: DEFINITIVE, STRONG, MODERATE, LIMITED Submitted by: G2P, Labcorp Genetics (formerly Invitae), ClinGen, Ambry Genetics
• pancreatic cancer, susceptibility to, 4

  Inheritance: AD Classification: MODERATE Submitted by: Genomics England PanelApp
• hereditary breast ovarian cancer syndrome

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• Fanconi anemia

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.89).
• BP6: Variant 17-43124230-A-G is Benign according to our data. Variant chr17-43124230-A-G is described in ClinVar as Benign. ClinVar VariationId is 125468.Status of the report is reviewed_by_expert_panel, 3 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.476 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
BRCA1	NM_007294.4	c.-19-115T>C		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.-19-115T>C		intron_variant	Intron 1 of 22	1	NM_007294.4	ENSP00000350283.3

Frequencies

GnomAD3 genomes AF: 0.317 AC: 48098 AN: 151962 Hom.: 7943 Cov.: 32

Gnomad AFR AF: 0.233

Gnomad AMI AF: 0.284

Gnomad AMR AF: 0.330

Gnomad ASJ AF: 0.358

Gnomad EAS AF: 0.370

Gnomad SAS AF: 0.493

Gnomad FIN AF: 0.404

Gnomad MID AF: 0.354

Gnomad NFE AF: 0.332

Gnomad OTH AF: 0.332

GnomAD4 exome AF: 0.349 AC: 181536 AN: 520800 Hom.: 32482 AF XY: 0.356 AC XY: 98755 AN XY: 277426

African (AFR) AF: 0.236 AC: 3155 AN: 13354

American (AMR) AF: 0.343 AC: 6496 AN: 18938

Ashkenazi Jewish (ASJ) AF: 0.368 AC: 5826 AN: 15820

East Asian (EAS) AF: 0.351 AC: 10632 AN: 30312

South Asian (SAS) AF: 0.503 AC: 22914 AN: 45520

European-Finnish (FIN) AF: 0.395 AC: 13589 AN: 34406

Middle Eastern (MID) AF: 0.380 AC: 823 AN: 2166

European-Non Finnish (NFE) AF: 0.327 AC: 108609 AN: 332410

Other (OTH) AF: 0.341 AC: 9492 AN: 27874

GnomAD4 genome AF: 0.316 AC: 48132 AN: 152080 Hom.: 7949 Cov.: 32 AF XY: 0.323 AC XY: 24010 AN XY: 74352

African (AFR) AF: 0.233 AC: 9671 AN: 41506

American (AMR) AF: 0.331 AC: 5052 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.358 AC: 1242 AN: 3470

East Asian (EAS) AF: 0.369 AC: 1912 AN: 5178

South Asian (SAS) AF: 0.492 AC: 2375 AN: 4824

European-Finnish (FIN) AF: 0.404 AC: 4265 AN: 10556

Middle Eastern (MID) AF: 0.354 AC: 104 AN: 294

European-Non Finnish (NFE) AF: 0.332 AC: 22543 AN: 67950

Other (OTH) AF: 0.336 AC: 709 AN: 2108

Alfa AF: 0.305 Hom.: 2360

Bravo AF: 0.303

Asia WGS AF: 0.410 AC: 1424 AN: 3474

ClinVar

Significance: Benign

Submissions summary: Uncertain:1 Benign:6

Revision: reviewed by expert panel

Submissions by phenotype

not specified Benign:3

-

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Nov 01, 2017

GeneKor MSA

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Clinical Genetics Laboratory, Department of Pathology, Netherlands Cancer Institute

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

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

Nov 25, 2003

Breast Cancer Information Core (BIC) (BRCA1)

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

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 0.3304 (Asian), 0.2154 (African), 0.3602 (European), derived from 1000 genomes (2012-04-30). -

not provided Benign:2

Jun 23, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	4.5
DANN	Benign	0.66
PhyloP100		-0.11
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs3765640; hg19: chr17-41276247; COSMIC: COSV58789216; COSMIC: COSV58789216;