chr17-43106452-A-G

Position:

• chr17-43106452-A-G

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 2P and 12B. PM2 BP4_Strong BP6_Very_Strong

The NM_007294.4(BRCA1):​c.212+4T>C variant causes a splice donor region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000211 in 1,420,212 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: BRCA1 NM_007294.4 splice_donor_region, intron
• Scores: Splicing: ADA: 0.0001773
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts U:1 B:6 O:1
• Conservation: PhyloP100: 0.172

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 -10 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.75).
• BP6: Variant 17-43106452-A-G is Benign according to our data. Variant chr17-43106452-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 183921.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
BRCA1	NM_007294.4	c.212+4T>C		splice_donor_region_variant, intron_variant		ENST00000357654.9	NP_009225.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
BRCA1	ENST00000357654.9	c.212+4T>C		splice_donor_region_variant, intron_variant		1	NM_007294.4	ENSP00000350283	P4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000803 AC: 2 AN: 249100 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 134666

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000885

Gnomad OTH exome AF: 0.000165

GnomAD4 exome AF: 0.00000211 AC: 3 AN: 1420212 Hom.: 0 Cov.: 27 AF XY: 0.00000141 AC XY: 1 AN XY: 708352

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.0000170

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000508 Hom.: 0

ClinVar

Significance: Benign/Likely benign

Submissions summary: Uncertain:1 Benign:6 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Hereditary cancer-predisposing syndrome Benign:3

Likely benign, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Dec 05, 2017	- -
Likely benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Dec 22, 2020	This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -
Likely benign, criteria provided, single submitter	curation	Sema4, Sema4	Apr 02, 2021	- -

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

Likely benign, criteria provided, single submitter	clinical testing	Counsyl	Aug 22, 2017	- -
not provided, no classification provided	in vitro	Brotman Baty Institute, University of Washington	-	- -

not provided Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

Department of Pathology and Laboratory Medicine, Sinai Health System

-

The BRCA1 c.212+4T>C variant has not been reported in the literature nor previously identified by our laboratory. This is an intronic variant residing within the consensus slice region, however it is not found to impact on splicing using the prediction programs. Another variant at c.212+3A>G reported 14 times, in BIC database, with unknown pathogenicity. In summary, based on the above information alone the clinical significance of this variant cannot be determined with certainty at the current time -

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

GeneDx

Oct 09, 2015

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 breast ovarian cancer syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 24, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.75
CADD	Benign	13
DANN	Benign	0.58

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00018
dbscSNV1_RF	Benign	0.018
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: rs398122652; hg19: chr17-41258469;