rs273902771

Positions:

• chr17-43099760-AC-A

Variant summary

Our verdict is Likely benign. Variant got -1 ACMG points: 0P and 1B. BP6

The NM_007294.4(BRCA1):​c.547+14delG variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000563 in 1,579,848 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.000053 (0 hom., cov: 31)
  • Exomes 𝑓: 0.000057 (0 hom.)
• Consequence: BRCA1 NM_007294.4 intron
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3 B:11
• Conservation: PhyloP100: -0.655

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 Likely_benign. Variant got -1 ACMG points.

• BP6: Variant 17-43099760-AC-A is Benign according to our data. Variant chr17-43099760-AC-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 125880.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=2, Likely_benign=4, Benign=3}. Variant chr17-43099760-AC-A is described in Lovd as [Benign]. Variant chr17-43099760-AC-A is described in Lovd as [Likely_benign].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
BRCA1	NM_007294.4	c.547+14delG		intron_variant		ENST00000357654.9	NP_009225.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
BRCA1	ENST00000357654.9	c.547+14delG		intron_variant		1	NM_007294.4	ENSP00000350283.3

Frequencies

GnomAD3 genomes AF: 0.0000526 AC: 8 AN: 152132 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000770

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000588

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000875 AC: 22 AN: 251350 Hom.: 0 AF XY: 0.0000736 AC XY: 10 AN XY: 135854

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000870

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000440

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000567 AC: 81 AN: 1427598 Hom.: 0 Cov.: 28 AF XY: 0.0000505 AC XY: 36 AN XY: 712352

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.000936

Gnomad4 SAS exome AF: 0.0000234

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000342

Gnomad4 OTH exome AF: 0.0000844

GnomAD4 genome AF: 0.0000525 AC: 8 AN: 152250 Hom.: 0 Cov.: 31 AF XY: 0.0000537 AC XY: 4 AN XY: 74440

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000772

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000588

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000364 Hom.: 0

Bravo AF: 0.0000604

Asia WGS AF: 0.00202 AC: 7 AN: 3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:3 Benign:11

Revision: criteria provided, conflicting classifications

Submissions by phenotype

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

Uncertain significance, no assertion criteria provided	clinical testing	Breast Cancer Information Core (BIC) (BRCA1)	Dec 17, 2010	- -
Likely benign, criteria provided, single submitter	clinical testing	Counsyl	Jul 24, 2017	- -
Likely benign, no assertion criteria provided	clinical testing	BRCAlab, Lund University	Mar 02, 2020	- -

not specified Benign:3

Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Feb 28, 2022	Variant summary: BRCA1 c.547+14delG involves the deletion of a non-conserved nucleotide located close to a canonical splice site which could affect mRNA splicing, leading to a significantly altered protein sequence. 4/4 computational tools predict no significant impact on normal splicing, and a functional study using a mini-gene system confirmed these predictions, showing no aberrant splicing (Steffensen_2014). The variant allele was found at a frequency of 0.00021 in 274964 control chromosomes (gnomAD v2.1 exomes dataset, and publication data), predominantly within the East Asian subpopulation at a frequency of 0.00087 in the gnomAD database. However, the variant was reported in some East Asian subpopulations with a much higher allele frequency, e.g. in the Korean population, the variant allele was found at a frequency of 0.0024. This frequency is 2.4 fold higher than the estimated maximum expected for a pathogenic variant in BRCA1 causing Hereditary Breast and Ovarian Cancer Syndrome (0.001), suggesting the variant is a benign polymorphism found primarily in East Asian subpopulations. c.547+14delG has been reported in the literature in individuals (most of them were from the Korean subpopulation), who were affected with breast- and/or ovarian cancer (e.g. Choi_2015, Ryu_2017, Ha_2020, Han_2020), however the variant was also reported in several healthy controls (e.g. Yoon_2016, Dong_2021). Co-occurrences with other pathogenic variants have been reported (e.g. c.5266dup (p.Gln1756ProfsX74), in the UMD database), providing supporting evidence for a benign role. In addition, in a study involving Korean individuals with a suspicion of high risk of familial breast-/ovarian cancer, multifactorial probability was estimated by performing systematic assessments of variants of unknown significance in the BRCA genes (which included analysis of co-occurrence with known deleterious mutations, personal and family history of cancer and tumor pathology), and predicted this variant to be benign (Park_2021). Six ClinVar submitters have assessed the variant since 2014: two classified the variant as benign, three as likely benign, and one as of uncertain significance. Based on the evidence outlined above, the variant was classified as benign. -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Likely benign, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	Aug 15, 2023	- -

not provided Benign:3

Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	This variant is associated with the following publications: (PMID: 28111427, 28364669) -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jun 01, 2024	BRCA1: BP4, BS1 -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics Laboratory, Department of Pathology, Netherlands Cancer Institute	-	- -

Hereditary cancer-predisposing syndrome Uncertain:1 Benign:1

Likely benign, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	May 07, 2015	- -
Uncertain significance, criteria provided, single submitter	curation	Sema4, Sema4	Nov 10, 2021	- -

Breast and/or ovarian cancer Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario

May 26, 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.547+14delG variant was identified in 3 of 796 proband chromosomes (frequency: 0.004) from Korean individuals or families with breast or ovarian cancer and was identified in 1 of 842 control chromosomes (frequency: 0.001) from healthy individuals (Choi 2015, Yoon 2016). A functional study using a minigene splicing assay found the variant had no effect on splicing and therefore was determined to be neutral (Steffensen_2014). The variant was also identified in dbSNP (ID: rs273902771) “With other allele”, ClinVar (classified with conflicting interpretations of pathogenicity; submitters: benign by Invitae, likely benign by Color Genomics Inc. and Laboratory Corporation of America, and uncertain significance by CHEO Genetics Diagnostic Laboratory and BIC), Clinvitae (3x), COGR (4 clinical laboratories with conflicting interpretations of pathogenicity), LOVD 3.0 (1x), and was not identified in Cosmic, MutDB, UMD-LSDB, BIC Database, ARUP Laboratories, Zhejiang Colon Cancer Database, the 1000 Genomes Project, the NHLBI GO Exome Sequencing Project, the Exome Aggregation Consortium (August 8th 2016), or the Genome Aggregation Database (Feb 27, 2017). The variant occurs outside of the splicing consensus sequence and 2 of 5 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) predict a greater than 10% difference in splicing; this is not very predictive of pathogenicity. 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

Jan 28, 2025

- -

Computational scores

Source: dbNSFP v4.3

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: rs273902771; hg19: chr17-41251777;