17-43063386-T-C

Position:

• chr17-43063386-T-C

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BP6_Very_Strong

The NM_007294.4(BRCA1):​c.5153-13A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000292 in 1,608,488 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 Benign (★★★).

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000032 (0 hom.)
• Consequence: BRCA1 NM_007294.4 intron
• Clinical Significance: Benign reviewed by expert panel U:2 B:9 O:1
• Conservation: PhyloP100: -0.114

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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.81).
• BP6: Variant 17-43063386-T-C is Benign according to our data. Variant chr17-43063386-T-C is described in ClinVar as [Benign]. Clinvar id is 125783.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr17-43063386-T-C is described in Lovd as [Benign].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
BRCA1	NM_007294.4	c.5153-13A>G		intron_variant		ENST00000357654.9	NP_009225.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
BRCA1	ENST00000357654.9	c.5153-13A>G		intron_variant		1	NM_007294.4	ENSP00000350283.3

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152166 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000160 AC: 4 AN: 250598 Hom.: 0 AF XY: 0.0000148 AC XY: 2 AN XY: 135502

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: 0.0000327

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000264

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000316 AC: 46 AN: 1456322 Hom.: 0 Cov.: 29 AF XY: 0.0000303 AC XY: 22 AN XY: 724902

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: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000397

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152166 Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1 AN XY: 74326

Gnomad4 AFR AF: 0.0000241

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000508 Hom.: 0

Bravo AF: 0.00000756

ClinVar

Significance: Benign

Submissions summary: Uncertain:2 Benign:9 Other:1

Revision: reviewed by expert panel

Submissions by phenotype

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

Benign, reviewed by expert panel	curation	Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA)	Aug 10, 2015	IARC class based on posterior probability from multifactorial likelihood analysis, thresholds for class as per Plon et al. 2008 (PMID: 18951446). Class 1 based on posterior probability = 0.0000517 -
Uncertain significance, no assertion criteria provided	clinical testing	Breast Cancer Information Core (BIC) (BRCA1)	Dec 30, 1999	- -
Likely benign, criteria provided, single submitter	clinical testing	Counsyl	Aug 22, 2017	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 27, 2017	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -
not provided, no classification provided	in vitro	Brotman Baty Institute, University of Washington	-	- -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	May 02, 2016	Variant summary: The c.5153-13A>G variant affects a non-conserved intronic nucleotide. Mutation taster predicts benign outcome for this variant. 5/5 in silico tools via Alamut predict this variant does not affect RNA splicing sites. Functional study showed that this variant does not affect splicing (Houdayer_BRCA1&2_HM_2012). This variant is found in 3/119788 control chromosomes at a frequency of 0.000025, which does not exceed maximal expected frequency of a pathogenic allele (0.0010005). This variant has been reported in BrC/OvC patients without evidence for causality. BIC lists one co-occurrence of variant of interest and a pathogenic BRCA1 variant in trans (c.5266dupC/p.Gln1756Profs, also cited in Judkins_2005), further supporting neutrality of our variant of interest. In addition, multiple clinical laboratory/publications classified this variant as benign. Taken together, this variant was classified as benign. -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 01, 2019	This variant is associated with the following publications: (PMID: 17924331, 21990134, 22505045, 16267036, 15829246, 30209399) -

Hereditary cancer-predisposing syndrome Benign:2

Benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Nov 18, 2014	This alteration is classified as 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	clinical testing	Color Diagnostics, LLC DBA Color Health	Mar 16, 2017	- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital

Aug 15, 2023

- -

Malignant tumor of breast Benign:1

Likely benign, no assertion criteria provided

clinical testing

Department of Pathology and Laboratory Medicine, Sinai Health System

-

The BRCA1 c.5153-13A>G variant was identified in the literature however the frequency of this variant in an affected population was not provided (Easton 2007, Houdayer 2012, Judkins 2005, Lindor 2012). The variant was also identified in dbSNP (ID: rs45471406) as "With Likely benign allele", ClinVar (classified as benign by Invitae, ENIGMA and Integrated Genetics/Laboratory Corporation of America; as likely benign by GeneDx, Color and Counsyl; as uncertain significance by BIC), and in LOVD 3.0 (4x ). The variant was identified in control databases in 4 of 245430 chromosomes at a frequency of 0.00002 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: European in 3 of 111414 chromosomes (freq: 0.00003), and South Asian in 1 of 30776 chromosomes (freq: 0.00003), while the variant was not observed in the African, Other, Latino, Ashkenazi Jewish, East Asian, and Finnish, populations. The variant occurs outside of the splicing consensus sequence and 1 of 4 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) predict a greater than 10% difference in splicing; this is not very predictive of pathogenicity. The variant was identified with a co-occurring pathogenic BRCA1 variant (c.5266dupC (Alias 5385insC) (p.Gln1756Profs)), increasing the likelihood that the c.5153-13A>G variant does not have clinical significance (Judkins 2005). In addition, several Multifactorial likelihood-ratio models showed the variant has odds in favor of neutrality 6799 and posterior probability of being deleterious 5.17√ó10‚àí5 (Easton 2007, Lindor 2012). In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time although we would lean towards a more benign role for this variant. This variant is classified as likely benign. -

Hereditary breast ovarian cancer syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Dec 28, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
CADD	Benign	12
DANN	Benign	0.67
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

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

Publications

LitVar

Other links and lift over

dbSNP: rs45471406; hg19: chr17-41215403;