rs796856605

chr17-43124027-A-ACTchr17-43124027-ACT-A

• Frequency: Genomes: not found (cov: 32)
• Consequence: BRCA1 NM_007294 frameshift
• Clinical Significance: Pathogenic reviewed by expert panel P:9
• Conservation: PhyloP100: 0.449

ACMG classification

Verdict is Pathogenic. Variant got 17 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. There are 3400 pathogenic variants in the truncated region.
• PM2: Very rare variant; Number of alleles below threshold, Median coverage is 32.
• PP5: Variant 17:43124027-A>ACT is Pathogenic according to our data. Variant chr17-43124027-A-ACT is described in ClinVar as [Pathogenic]. Clinvar id is 55667. Status of the report is reviewed_by_expert_panel, 3 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
BRCA1	NM_007294.4	c.69_70insAG	p.Cys24SerfsTer8	frameshift_variant	2/23	ENST00000357654.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
BRCA1	ENST00000357654.9	c.69_70insAG	p.Cys24SerfsTer8	frameshift_variant	2/23	1	NM_007294.4	P2

Frequencies

GnomAD3 genomes Cov.: 32

Bravo AF: 0.00000378

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:9

Revision: reviewed by expert panel

LINK:

Submissions by phenotype

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

Pathogenic, no assertion criteria provided	clinical testing	Sharing Clinical Reports Project (SCRP)	Jan 25, 2011	- -
Pathogenic, no assertion criteria provided	clinical testing	Breast Cancer Information Core (BIC) (BRCA1)	May 29, 2002	- -
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. -

not provided Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Feb 10, 2017	This duplication of two nucleotides in BRCA1 is denoted c.68_69dupAG at the cDNA level and p.Cys24SerfsX8 (C24SfsX8) at the protein level. Using alternate nomenclature, this variant would also be defined as BRCA1 187_188dupAG or 69_70insAG. The normal sequence, with the bases that are duplicated in brackets, is TTAG[dupAG]TGTC. The duplication causes a frameshift which changes a Cysteine to a Serine at codon 24, and creates a premature stop codon at position 8 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.68_69dupAG has been published in association with at least three cases of breast cancer (Borg 2010, Dean 2015). We consider this variant to be pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Jul 30, 2019	The variant results in a shift of the reading frame, and is therefore predicted to result in the loss of a functional protein. Found in at least one symptomatic patient, and not found in general population data. -

Hereditary breast ovarian cancer syndrome Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	May 23, 2019	Variant summary: BRCA1 c.68_69dupAG (p.Cys24SerfsX8) 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 (gnomAD). c.68_69dupAG has been reported in the literature in individuals affected with Hereditary Breast and Ovarian Cancer (Borg_2010, Dean_2015, Judkins_2005, Quezada Urban_2018). These data indicate that the variant is likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Four ClinVar submitters including an expert panel (ENIGMA) (evaluation after 2014) cite the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Jul 06, 2022	This sequence change creates a premature translational stop signal (p.Cys24Serfs*8) 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). This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with contralateral breast cancer (PMID: 20104584). ClinVar contains an entry for this variant (Variation ID: 55667). For these reasons, this variant has been classified as Pathogenic. -

Familial cancer of breast;C2676676:Breast-ovarian cancer, familial, susceptibility to, 1;C3280442:Pancreatic cancer, susceptibility to, 4;C4554406:Fanconi anemia, complementation group S Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Apr 10, 2022

- -

Hereditary cancer-predisposing syndrome Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 11, 2020

The c.68_69dupAG pathogenic mutation, located in coding exon 1 of the BRCA1 gene, results from a duplication of AG at nucleotide position 68, causing a translational frameshift with a predicted alternate stop codon (p.C24Sfs*8). This alteration has been reported in several breast cancer patients (Borg A et al. Hum. Mutat., 2010 Mar;31:E1200-40; Dean M et al. Gigascience, 2015 Nov;4:50; Quezada Urban R et al. Cancers (Basel), 2018 Sep;10:; Millan Catalan O et al. Cancers (Basel), 2019 Aug;11:). Of note, this alteration is also designated as 188insAG in published literature. 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. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs80357914; hg19: chr17-41276044;