17-43090944-C-T

Variant names:

• chr17-43090944-C-T
• rs80356857
• NM_007294.4:c.4185G>A

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM2 PP3_Strong PP5_Very_Strong

The NM_007294.4(BRCA1):​c.4185G>A​(p.Gln1395Gln) variant causes a splice region, synonymous change. The variant allele was found at a frequency of 0.00000137 in 1,456,040 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Pathogenic (★★★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: BRCA1 NM_007294.4 splice_region, synonymous
• Scores: Splicing: ADA: 1.000
• Clinical Significance: Pathogenic reviewed by expert panel P:9
• Conservation: PhyloP100: 4.83

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 Pathogenic. Variant got 14 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF, max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.
• PP5: Variant 17-43090944-C-T is Pathogenic according to our data. Variant chr17-43090944-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 55131.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr17-43090944-C-T is described in Lovd as [Pathogenic]. Variant chr17-43090944-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
BRCA1	NM_007294.4	c.4185G>A	p.Gln1395Gln	splice_region_variant, synonymous_variant	Exon 11 of 23	ENST00000357654.9	NP_009225.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
BRCA1	ENST00000357654.9	c.4185G>A	p.Gln1395Gln	splice_region_variant, synonymous_variant	Exon 11 of 23	1	NM_007294.4	ENSP00000350283.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1456040 Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1 AN XY: 723664

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: 0.00000180

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:9

Revision: reviewed by expert panel

Submissions by phenotype

Breast-ovarian cancer, familial, susceptibility to, 1 Pathogenic:3

Oct 02, 2015

Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

May 29, 2002

Breast Cancer Information Core (BIC) (BRCA1)

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Jun 18, 2019

Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA)

Significance: Pathogenic

Review Status: reviewed by expert panel

Collection Method: curation

IARC class based on posterior probability from multifactorial likelihood analysis, thresholds for class as per Plon et al. 2008 (PMID: 18951446). Class 5 based on posterior probability = 0.999943 -

not provided Pathogenic:2

-

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

The BRCA1 p.Gln1395= variant was identified in 21 of 55,604 proband chromosomes (frequency: 0.0004) from individuals or families with hereditary breast and ovarian cancer and was not identified in 22,482 control chromosomes from healthy individuals (Momozawa 2018, Rebbeck 2018, Palmero 2018, Claes 2003, Wappenschmidt 2012, Machackova 2008, Meindl 2002, Gayther 1999, Eccles 1998). The variant was identified in dbSNP (rs80356857) as “with pathogenic, uncertain significance allele”, ClinVar (classified as pathogenic by Ambry Genetics, BIC, Integrated Genetics, CIMBA and Quest Diagnostics), LOVD 3.0 (observed 7x) and UMD-LSDB (observed 2x). This variant was identified in a Czech family in three family members diagnosed with unilateral or bilateral breast cancer in their 40s (Claes 2003). The variant was not identified in the following control databases: the Exome Aggregation Consortium (August 8th 2016) or the Genome Aggregation Database (Feb 27, 2017). The variant occurs in the last base of the exon and 4 of 4 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) predict a greater than 10% difference in splicing. RT-PCR assays demonstrated that the variant weakens a 3’ splice site leading to skipping of exon 12 (Claes 2003, Wappenschmidt 2012). Exon 12 skipping is predicted to lead to an out-of-frame deletion, which would result in an absent or truncated protein and loss of BRCA1 function. Loss of function variants of the BRCA1 gene are an established mechanism of disease in hereditary breast and ovarian cancer syndrome and is the type of variant expected to cause the disorder. In summary, based on the above information this variant meets our laboratory’s criteria to be classified as pathogenic. -

Sep 14, 2015

Quest Diagnostics Nichols Institute San Juan Capistrano

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Hereditary cancer-predisposing syndrome Pathogenic:2

Oct 13, 2020

Color Diagnostics, LLC DBA Color Health

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant disrupts the conserved last nucleotide in exon 11 of the BRCA1 gene, and it is predicted to disrupt splicing. This variant is also known as 4304G>A in the literature. RNA studies have shown that this variant causes an out-of-frame skipping of exon 11 (PMID: 12759930, 23239986), and an analysis of cDNA from a carrier suggests that that variant transcript is not stably expressed (PMID: 7493024). This variant has been observed in multiple individuals and families affected with breast and ovarian cancer (PMID: 7493024, 9649133, 11802209, 12759930, 23239986, 29907814). Family testing that included at least six families reported cosegregation of the variant with disease with a likelihood ratio of 39.3167 (PMID: 7493024, 31131967). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Loss of BRCA1 function is a known mechanism of disease (clinicalgenome.org). Based on the available evidence, this variant is classified as Pathogenic. -

Feb 19, 2016

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.4185G>A pathogenic mutation (also known as p.Q1395Q), located in coding exon 10 of the BRCA1 gene, results from a G to A substitution at nucleotide position 4185. This nucleotide substitution does not change the codon at 1395. However, this change occurs in the last base pair of coding exon 10, which makes it likely to have some effect on normal mRNA splicing. This mutation was first reported in two breast and/or ovarian cancer families from the United Kingdom (Gayther SA et al. Nat Genet. 1995 Dec;11(4):428-33). Analysis of cDNA from an affected individual indicated a splicing defect and segregation analysis of one of the families showed complete segregation of the mutation with disease. Subsequently, this mutation has been described in several other breast and/or ovarian cancer families and functional studies have confirmed that the mutation results in an aberrant transcript due to skipping of coding exon 10 (Eccles DM et al. Br J Cancer. 1998 Jun;77(12):2199-203; Meindl A et al. Int J Cancer. 2002 Feb 1;97(4):472-80; Claes K et al. Genes Chromosomes Cancer. 2003 Jul;37(3):314-20; Wappenschmidt B et al. PLoS One. 2012;7(12):e50800). Of note, this mutation is also designated as 4304G>A in published literature. Based on the available evidence, c.4185G>A is classified as a pathogenic mutation. -

Hereditary breast ovarian cancer syndrome Pathogenic:2

Nov 30, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change affects codon 1395 of the BRCA1 mRNA. It is a 'silent' change, meaning that it does not change the encoded amino acid sequence of the BRCA1 protein. RNA analysis indicates that this variant induces altered splicing and may result in an absent or altered protein product. This variant is not present in population databases (gnomAD no frequency). This variant has been observed in individual(s) with breast cancer and/or ovarian cancer (PMID: 7493024, 9649133, 12759930, 23239986). It has also been observed to segregate with disease in related individuals. This variant is also known as 4304G>A. ClinVar contains an entry for this variant (Variation ID: 55131). Based on a multifactorial likelihood algorithm using genetic, in silico, and/or statistical data, this variant has been determined to have a high probability of being pathogenic (PMID: 31131967). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Studies have shown that this variant results in skipping of exon 11 (also known as exon 12), and produces a non-functional protein and/or introduces a premature termination codon (PMID: 7493024, 12759930, 23239986). For these reasons, this variant has been classified as Pathogenic. -

Nov 26, 2018

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: BRCA1 c.4185G>A (p.Gln1395Gln) alters a conserved nucleotide located at the last nucleotide of an exon and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. Several computational tools predict a significant impact on normal splicing: Five predict the variant abolishes/weakens a 5' splicing donor site. Four predict the variant abolishes/weakens a 3' acceptor site. Multiple publications report experimental evidence that this variant affects mRNA splicing (Claes_2003, Wappenschmidt_2012) and one reports reduced expression of BRCA1 protein levels (Taylor_1998). The variant was absent in 237624 control chromosomes (gnomAD) and has been reported in the literature in multiple individuals affected with Hereditary Breast and Ovarian Cancer (Claes_2003, Wang_2014, Palmero _2018, Wappenschmidt_2012) . These data indicate that the variant is very likely to be associated with disease. Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories have classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.25
CADD	Benign	22
DANN	Benign	0.94

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	1.0
SpliceAI score (max)		0.93		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.93		Position offset: 0

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs80356857; hg19: chr17-41242961;