rs80358014

Positions:

• chr17-43097306-C-A

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.548-17G>T variant causes a splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000289 in 1,606,792 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 0.00027 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00029 (0 hom.)
• Consequence: BRCA1 NM_007294.4 splice_polypyrimidine_tract, intron
• Clinical Significance: Benign reviewed by expert panel U:1 B:21
• Conservation: PhyloP100: 0.773

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=-0.8).
• BP6: Variant 17-43097306-C-A is Benign according to our data. Variant chr17-43097306-C-A is described in ClinVar as [Benign]. Clinvar id is 37675.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr17-43097306-C-A is described in Lovd as [Benign].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
BRCA1	NM_007294.4	c.548-17G>T		splice_polypyrimidine_tract_variant, intron_variant		ENST00000357654.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
BRCA1	ENST00000357654.9	c.548-17G>T		splice_polypyrimidine_tract_variant, intron_variant		1	NM_007294.4	P4

Frequencies

GnomAD3 genomes AF: 0.000270 AC: 41 AN: 151628 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000484

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000658

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0000953

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000545

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000208 AC: 52 AN: 249716 Hom.: 0 AF XY: 0.000170 AC XY: 23 AN XY: 135406

Gnomad AFR exome AF: 0.0000635

Gnomad AMR exome AF: 0.0000872

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000131

Gnomad FIN exome AF: 0.0000924

Gnomad NFE exome AF: 0.000363

Gnomad OTH exome AF: 0.000165

GnomAD4 exome AF: 0.000291 AC: 423 AN: 1455046 Hom.: 0 Cov.: 29 AF XY: 0.000282 AC XY: 204 AN XY: 724256

Gnomad4 AFR exome AF: 0.0000601

Gnomad4 AMR exome AF: 0.0000224

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000256

Gnomad4 FIN exome AF: 0.0000375

Gnomad4 NFE exome AF: 0.000335

Gnomad4 OTH exome AF: 0.000416

GnomAD4 genome AF: 0.000270 AC: 41 AN: 151746 Hom.: 0 Cov.: 33 AF XY: 0.000148 AC XY: 11 AN XY: 74118

Gnomad4 AFR AF: 0.0000483

Gnomad4 AMR AF: 0.0000657

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.0000953

Gnomad4 NFE AF: 0.000545

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000318 Hom.: 0

Bravo AF: 0.000257

ClinVar

Significance: Benign

Submissions summary: Uncertain:1 Benign:21

Revision: reviewed by expert panel

Submissions by phenotype

Breast-ovarian cancer, familial, susceptibility to, 1 Uncertain:1 Benign:6

Benign, criteria provided, single submitter	clinical testing	Counsyl	Apr 06, 2016	- -
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 = 0.000000319 -
Uncertain significance, no assertion criteria provided	clinical testing	Breast Cancer Information Core (BIC) (BRCA1)	May 29, 2002	- -
Benign, criteria provided, single submitter	clinical testing	KCCC/NGS Laboratory, Kuwait Cancer Control Center	Jul 07, 2023	- -
Likely benign, no assertion criteria provided	clinical testing	Department of Medical Genetics, University Hospital of North Norway	May 01, 2016	- -
Benign, no assertion criteria provided	clinical testing	Sharing Clinical Reports Project (SCRP)	Apr 17, 2009	- -
Benign, no assertion criteria provided	clinical testing	BRCAlab, Lund University	Mar 02, 2020	- -

not specified Benign:7

Benign, no assertion criteria provided	clinical testing	Clinical Genetics Laboratory, Department of Pathology, Netherlands Cancer Institute	-	- -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Benign, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	Aug 15, 2023	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	Jun 29, 2017	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Feb 24, 2014	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. -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -

not provided Benign:3

Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Mar 28, 2023	- -
Likely benign, no assertion criteria provided	clinical testing	Department of Pathology and Laboratory Medicine, Sinai Health System	-	The BRCA1 c.548-17G>T variant was identified in ClinVar (Bengin. Classified as benign by ENIGMA, Prevention Genetics, Invitae, Counsyl, ARUP Laboratories, Integrated Genetics, GeneDx, Centre for Mendelian Genomics at University Medical Centre Ljubljana, SCRP. Classified as likely benign by Department of Medical Genetics at University Hospital North Norway, COGR. Classified as VUS by BIC). The variant was identified in dnSNP (rs80358014). The variant has been reporting as co-occuring with pathogenic variants (BRCA1, c.2722G>T and BRCA2 variants, c.8237_8238delCA (p.Thr2736SerfsX17), c.2930_2940del and c.1202C>A (p.Ser401X), SCV000699264.1). The variant was identified in control databases in 59 of 280930 chromosomes (0 homozygous) at a frequency of 0.0002100 and was observed at the highest frequency in the European (non-Finnish) population in 47 of 128348 chromosomes (freq: 0.0003662) (Genome Aggregation Database March 6, 2019, v2.1.1).The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (Splice AI exome) do not predict a deleterious effect on splicing. 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. -
Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jun 07, 2016	Variant summary: The BRCA1 c.548-17G>T variant causing the alteration of a non-conserved intronic nucleotide with 5/5 in silico programs predicting no significant effect on splicing, which is supported by multiple functional studies. This variant was observed in the large, broad control population, ExAC, with an allele frequency of 20/119928 (1/5995, frequency: 0.0001668), which does not exceed the estimated maximal expected allele frequency for a pathogenic BRCA1 variant of 1/1000 (0.0010005). The variant of interest has been reported in multiple affected individuals via publications with limited information (ie, lack of co-occurrence and cosegregation data). However, the variant has been reported to co-occur with other pathogenic variants, BRCA1, c.2722G>T and BRCA2 variants, c.8237_8238delCA (p.Thr2736SerfsX17), c.2930_2940del and c.1202C>A (p.Ser401X). In addition, multiple publications and reputable databases/clinical laboratories cite the variant as "Benign/Neutral." Therefore, taking all available lines of evidence into consideration, the variant of interest has been classified as Benign. -

Hereditary cancer-predisposing syndrome Benign:2

Benign, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Feb 23, 2015	- -
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. -

Breast and/or ovarian cancer Benign:1

Likely benign, criteria provided, single submitter

clinical testing

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

Mar 23, 2023

- -

Familial cancer of breast Benign:1

Benign, criteria provided, single submitter

clinical testing

Centre for Mendelian Genomics, University Medical Centre Ljubljana

Oct 17, 2019

This variant was classified as: Benign. The following ACMG criteria were applied in classifying this variant: BP6,BP4. -

Hereditary breast ovarian cancer syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 29, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.80
CADD	Benign	2.2
DANN	Benign	0.35

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: rs80358014; hg19: chr17-41249323;