17-43051131-G-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.5278-14C>G 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 0.0000739 in 1,611,186 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 0.000072 (0 hom., cov: 31)
  • Exomes 𝑓: 0.000074 (0 hom.)
• Consequence: BRCA1 NM_007294.4 splice_polypyrimidine_tract, intron
• Clinical Significance: Benign reviewed by expert panel U:1 B:16 O:1
• Conservation: PhyloP100: 0.289

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=-0.78).
• BP6: Variant 17-43051131-G-C is Benign according to our data. Variant chr17-43051131-G-C is described in ClinVar as [Benign]. Clinvar id is 91645.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr17-43051131-G-C is described in Lovd as [Likely_benign].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
BRCA1	NM_007294.4	c.5278-14C>G		splice_polypyrimidine_tract_variant, intron_variant		ENST00000357654.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
BRCA1	ENST00000357654.9	c.5278-14C>G		splice_polypyrimidine_tract_variant, intron_variant		1	NM_007294.4	P4

Frequencies

GnomAD3 genomes AF: 0.0000723 AC: 11 AN: 152128 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.0000483

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: 0.000132

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000319 AC: 8 AN: 250986 Hom.: 0 AF XY: 0.0000368 AC XY: 5 AN XY: 135754

Gnomad AFR exome AF: 0.0000618

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: 0.0000617

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000740 AC: 108 AN: 1459058 Hom.: 0 Cov.: 30 AF XY: 0.0000785 AC XY: 57 AN XY: 726068

Gnomad4 AFR exome AF: 0.0000299

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000919

Gnomad4 OTH exome AF: 0.0000663

GnomAD4 genome AF: 0.0000723 AC: 11 AN: 152128 Hom.: 0 Cov.: 31 AF XY: 0.0000538 AC XY: 4 AN XY: 74312

Gnomad4 AFR AF: 0.0000483

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: 0.000132

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000712 Hom.: 0

Bravo AF: 0.0000907

ClinVar

Significance: Benign

Submissions summary: Uncertain:1 Benign:16 Other:1

Revision: reviewed by expert panel

Submissions by phenotype

Breast-ovarian cancer, familial, susceptibility to, 1 Uncertain:1 Benign:7 Other:1

Likely benign, no assertion criteria provided	clinical testing	Sharing Clinical Reports Project (SCRP)	Jan 18, 2011	- -
Benign, reviewed by expert panel	curation	Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA)	Jun 18, 2019	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 = 7.93E-10 -
Uncertain significance, no assertion criteria provided	clinical testing	Breast Cancer Information Core (BIC) (BRCA1)	May 29, 2002	- -
Likely benign, criteria provided, single submitter	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	Sep 21, 2015	- -
Likely benign, criteria provided, single submitter	literature only	Counsyl	Mar 12, 2014	- -
Benign, no assertion criteria provided	clinical testing	BRCAlab, Lund University	Mar 02, 2020	- -
Likely benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
not provided, no classification provided	in vitro	Brotman Baty Institute, University of Washington	-	- -
Likely benign, criteria provided, single submitter	clinical testing	Michigan Medical Genetics Laboratories, University of Michigan	Nov 03, 2014	- -

not specified Benign:4

Benign, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	Aug 15, 2023	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 19, 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. -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jan 14, 2022	Variant summary: BRCA1 c.5278-14C>G alters a non-conserved nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. 4/4 computational tools predict no significant impact on normal splicing. These predictions have been confirmed by functional studies demonstrating the variant has no splicing effect (Spearman_2008, Whiley_2011, Wappenschmidt_2012, Steffensen_2014). The variant allele was found at a frequency of 3.2e-05 in 250986 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.5278-14C>G has been reported in the literature in individuals affected with cancer including breast cancer and pancreatic cancer (van der Hout_2006, Spearman_2008, Axilbund_2009, Lu_2012). These reports do not provide unequivocal conclusions about association of the variant with Hereditary Breast and Ovarian Cancer. Co-occurrences with pathogenic variants have been reported (BRCA2 c.5722_5723delCT, p.Leu1908ArgfsX2 [BIC]; BRCA2 unspecified [van der Hout_2006]), providing supporting evidence for a benign role. Experimental evidence evaluating an impact on protein function through utilization of a cell-survival assay in a population of edited haploid HAP1 cells as a measure of functional HDR pathway, reported the variant to be functional (Findlay_2018). Six ClinVar submitters including an expert panel (ENIGMA) (evaluation after 2014) cite the variant as benign/likely benign. Based on the evidence outlined above, the variant was classified as benign. -

not provided Benign:1

Likely benign, no assertion criteria provided

clinical testing

Clinical Genetics Laboratory, Department of Pathology, Netherlands Cancer Institute

-

- -

Malignant tumor of breast Benign:1

Likely benign, no assertion criteria provided

clinical testing

Department of Pathology and Laboratory Medicine, Sinai Health System

-

The c.5278-14C>G variant was identified in 5 of 8294 proband chromosomes (frequency: 0.001) from individuals or families with breast, ovarian and pancreatic cancer (Axilbund 2009, Spearman 2008, van der Hout 2006). The variant was also identified in dbSNP (ID: rs80358105), NHLBI Exome Sequencing Project (Exome Variant Server), Exome Aggregation Consortium (ExAC) database, LOVD, the ClinVar database (classified as a likely benign variant by the Sharing Clinical Reports Project (derived from Myriad reports) and Counsyl; classified as unknown clinical importance by BIC), the BIC database (4X with unknown clinical importance), and UMD (3X as an uncertain significance variant). This variant was identified in the Exome Variant Server project in 3 of 13006 European American/African American alleles, the Exome Aggregation Consortium (ExAC) database (released Oct 20th, 2014) in 4 of 76380 chromosomes (4 individuals) from a population of European (Non-Finnish) and African individuals, although this low number of observations is not substantive enough to determine its relationship to disease. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) do not predict a difference in splicing. Four studies have predicted the variant has no effect on splicing (Spearman 2008, Steffensen 2014, van der Hout 2006, Whiley 2011) and two of them classified it as neutral (Steffensen 2014, van der Hout 2006). 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 predicted benign. -

Hereditary cancer-predisposing syndrome Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Color Diagnostics, LLC DBA Color Health

Jul 20, 2015

- -

Familial cancer of breast Benign:1

Benign, criteria provided, single submitter

clinical testing

Baylor Genetics

Feb 23, 2017

- -

Hereditary breast ovarian cancer syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 27, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.78
Cadd	Benign	14
Dann	Benign	0.76
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.2

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

Publications

LitVar

Other links and lift over

dbSNP: rs80358105; hg19: chr17-41203148;