rs80357927

chr17-43093718-CT-C

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_007294.4(BRCA1):c.1812del(p.Ala605HisfsTer7) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★★★). Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 32)
• Consequence: BRCA1 NM_007294.4 frameshift
• Clinical Significance: Pathogenic reviewed by expert panel P:11
• Conservation: PhyloP100: -0.249

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 18 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 17-43093718-CT-C is Pathogenic according to our data. Variant chr17-43093718-CT-C is described in ClinVar as [Pathogenic]. Clinvar id is 125513.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr17-43093718-CT-C is described in Lovd as [Pathogenic]. Variant chr17-43093718-CT-C is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
BRCA1	NM_007294.4	c.1812del	p.Ala605HisfsTer7	frameshift_variant	10/23	ENST00000357654.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
BRCA1	ENST00000357654.9	c.1812del	p.Ala605HisfsTer7	frameshift_variant	10/23	1	NM_007294.4	P4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 34

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:11

Revision: reviewed by expert panel

Submissions by phenotype

Breast-ovarian cancer, familial, susceptibility to, 1 Pathogenic:4

Pathogenic, reviewed by expert panel	curation	Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA)	Sep 08, 2016	Variant allele predicted to encode a truncated non-functional protein. -
Pathogenic, criteria provided, single submitter	clinical testing	Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge	Oct 02, 2015	- -
Pathogenic, no assertion criteria provided	clinical testing	Breast Cancer Information Core (BIC) (BRCA1)	Oct 29, 2001	- -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Dec 07, 2022	- -

Hereditary breast ovarian cancer syndrome Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Feb 08, 2016	The p.Ala605fs variant in BRCA1 has been reported in 1 individual with breast an d colon cancer (Susswein 2015). It was absent from large population studies, tho ugh the ability of these studies to accurately detect indels may be limited. Thi s variant is predicted to cause a frameshift, which alters the protein?s amino a cid sequence beginning at position 605 and leads to a premature termination codo n 7 amino acids downstream. This alteration is then predicted to lead to a trunc ated or absent protein. Heterozygous loss of function of the BRCA1 gene is an es tablished disease mechanism for hereditary breast and ovarian cancer (HBOC). In summary, this variant meets our criteria to be classified as pathogenic for auto somal dominant HBOC. -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	May 03, 2023	ClinVar contains an entry for this variant (Variation ID: 125513). For these reasons, this variant has been classified as Pathogenic. This premature translational stop signal has been observed in individual(s) with breast and colon cancer and a personal and/or family history of breast and ovarian cancer (PMID: 26681312, 29446198). This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Ala605Hisfs*7) in the BRCA1 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in BRCA1 are known to be pathogenic (PMID: 20104584). -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Dec 18, 2023	Variant summary: BRCA1 c.1812delA (p.Ala605HisfsX7) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. The variant was absent in 251050 control chromosomes. c.1812delA has been reported in the literature in individuals affected with a history of Breast and Colon cancer (Susswein_2016). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publication have been ascertained in the context of this evaluation (PMID: 26681312). Eight submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -

not provided Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Mar 23, 2018	This frameshift variant causes the premature termination of BRCA1 protein synthesis. In addition, it has been reported in an individual with breast and colon cancer in the published literature (PMID: 26681312 (2015)). Based on the available information, this variant is classified as pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Oct 09, 2017	This deletion of one nucleotide is denoted BRCA1 c.1812delA at the cDNA level and p.Ala605HisfsX7 (A605HfsX7) at the protein level. Using alternate nomenclature, this variant would be defined as BRCA1 1931delA. The normal sequence, with the base that is deleted in brackets, is CAAA[delA]GCAC. The deletion causes a frameshift, which changes an Alanine to a Histidine at codon 605, and creates a premature stop codon at position 7 of the new reading frame. This variant is predicted to cause loss of normal protein function through either protein truncation or nonsense-mediated mRNA decay. BRCA1 c.1812delA has been observed in at least one individual with a personal history of breast and colon cancer (Susswein 2016). We considered this variant to be pathogenic. -

Hereditary cancer-predisposing syndrome Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Ambry Genetics	Apr 13, 2023	The c.1812delA pathogenic mutation, located in coding exon 9 of the BRCA1 gene, results from a deletion of one nucleotide at nucleotide position 1812, causing a translational frameshift with a predicted alternate stop codon (p.A605Hfs*7). This alteration was detected in one individual with breast and colon cancer undergoing clinical hereditary cancer panel testing and in one individual undergoing whole exome sequencing (Susswein LR et al. Genet. Med. 2016 Aug;18(8):823-32; Buchanan AH et al. Genet. Med., 2018 04;20:554-558). Additionally, this alteration was identified in a large, worldwide study of BRCA1/2 mutation positive families (Rebbeck TR et al. Hum. Mutat., 2018 05;39:593-620). In addition to the clinical data presented in the literature, this alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation. -
Pathogenic, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Dec 28, 2020	This variant deletes 1 nucleotide in exon 10 of the BRCA1 gene, creating a frameshift and premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. To our knowledge, functional studies have not been reported for this variant. This variant has been observed in one individual affected with breast and colon cancer and another individual affected with fallopian tube cancer (PMID: 26681312, 29261187). 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. -

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: rs80357927; hg19: chr17-41245735;