rs431825390

Positions:

• chr17-43093198-C-CCA

Variant summary

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

The ENST00000357654.9(BRCA1):​c.2332_2333insTG​(p.Gly778ValfsTer15) 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 (★★★). Synonymous variant affecting the same amino acid position (i.e. G778G) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 32)
• Consequence: BRCA1 ENST00000357654.9 frameshift
• Clinical Significance: Pathogenic reviewed by expert panel P:8
• Conservation: PhyloP100: -0.100

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 17-43093198-C-CCA is Pathogenic according to our data. Variant chr17-43093198-C-CCA is described in ClinVar as [Pathogenic]. Clinvar id is 252382.Status of the report is reviewed_by_expert_panel, 3 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
BRCA1	NM_007294.4	c.2332_2333insTG	p.Gly778ValfsTer15	frameshift_variant	10/23	ENST00000357654.9	NP_009225.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
BRCA1	ENST00000357654.9	c.2332_2333insTG	p.Gly778ValfsTer15	frameshift_variant	10/23	1	NM_007294.4	ENSP00000350283	P4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 42

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:8

Revision: reviewed by expert panel

Submissions by phenotype

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

Likely pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Feb 14, 2023	- -
Pathogenic, no assertion criteria provided	clinical testing	Sharing Clinical Reports Project (SCRP)	Oct 17, 2011	- -
Pathogenic, reviewed by expert panel	curation	Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA)	Dec 15, 2017	Variant allele predicted to encode a truncated non-functional protein. -
Pathogenic, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Sep 25, 2015	- -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

May 06, 2016

This duplication of two nucleotides is denoted BRCA1 c.2331_2332dupTG at the cDNA level and p.Gly778ValfsX15 (G778VfsX15) at the protein level. This variant is also known as BRCA1 2450_2451dupTG or 2451insTG using alternate nomenclature. The normal sequence, with the bases that are duplicated in braces, is ATTA[TG]GCAC. The duplication causes a frameshift, which changes a Glycine to a Valine at codon 778, and creates a premature stop codon at position 15 of the new reading frame. Although this variant has not, to our knowledge, been reported in the literature, it is predicted to cause loss of normal protein function through either protein truncation or nonsense-mediated mRNA decay. We consider this variant to be pathogenic. -

Hereditary cancer-predisposing syndrome Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 28, 2016

The c.2331_2332dupTG pathogenic mutation, located in coding exon 9 of the BRCA1 gene, results from a duplication of TG at nucleotide position 2331, causing a translational frameshift with a predicted alternate stop codon. 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. -

Familial cancer of breast Pathogenic:1

Pathogenic, flagged submission

clinical testing

GeneDx

Jun 25, 2014

This insertion of 2 nucleotides is denoted BRCA1 c.2332_2333insTG (a.k.a c.2331_2332dupTG) at the cDNA level and p.Gly778ValfsX15 (G778VfsX15) at the protein level. The normal sequence, with the bases that are inserted in brackets, is TATG{insTG}GCAC. The insertion causes a frameshift, which changes a Glycine to a Valine at codon 778 in exon 10, and creates a premature stop codon at position 15 of the new reading frame. This mutation is also known as BRCA1 2451insTG using alternate nomenclature. Although this mutation has not, to our knowledge, been reported in the literature, it is predicted to cause loss of normal protein function through either protein truncation or nonsense-mediated mRNA decay. We consider this mutation to be pathogenic. and is indicative of Hereditary Breast and Ovarian Cancer (HBOC), an autosomal dominant condition that predisposes to early onset breast cancer, ovarian and fallopian tube cancer, as well as other cancers. Breast and ovarian cancer are the predominant BRCA1-related cancers that unaffected female mutation carriers are at risk to develop. The lifetime risk for breast cancer is estimated to be 57 to 84% and the lifetime risk for ovarian cancer is estimated to be 24 to 54% (Antoniou 2003, Chen 2007, Ford 1998). BRCA1 mutations have also been reported in women with fallopian tube carcinoma, primary peritoneal carcinoma, and uterine serous carcinoma (Levine 2003, Pennington 2013). Graeser et al. (2009) found that women who harbor a pathogenic BRCA1 mutation have an increased risk for contralateral breast cancer that is dependent on age at initial diagnosis. It is estimated that the risk to develop a second breast cancer within 10 years of the first diagnosis if initially diagnosed less than age 40 years of age is 31%, between the ages of 40 and 50 is 11% and after the age of 50 is 8%. Additionally, it is estimated that the risk to develop a second breast cancer within 25 years of their first diagnosis if initially diagnosed less than age 40 years of age is 63%, between the ages of 40 and 50 is 44% and after the age of 50 is 20%. Other cancer risks associated with a BRCA1 pathogenic variant include approximately a 20% risk for prostate cancer in male carriers (Thompson 2002), a 4% risk for male breast cancer (Liede 2004), and an estimated 1 to 3% risk for pancreatic cancer in both men and women (Brose 2002, Thompson 2002). The variant is found in BRCA panel(s). -

Hereditary breast ovarian cancer syndrome Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Sep 18, 2022

This variant is not present in population databases (gnomAD no frequency). For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 252382). This variant has not been reported in the literature in individuals affected with BRCA1-related conditions. This sequence change creates a premature translational stop signal (p.Gly778Valfs*15) 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). -

Computational scores

Source: dbNSFP v4.3

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs431825390; hg19: chr17-41245215;