rs80357902

Variant names:

• chr17-43091882-A-AT
• rs80357902
• NM_007294.4:c.3648dupA

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.3648dupA​(p.Ser1217IlefsTer2) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,870 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★★★). Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: BRCA1 NM_007294.4 frameshift
• Clinical Significance: Pathogenic reviewed by expert panel P:18
• Conservation: PhyloP100: -1.88

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 17-43091882-A-AT is Pathogenic according to our data. Variant chr17-43091882-A-AT is described in ClinVar as [Pathogenic]. Clinvar id is 37535.Status of the report is reviewed_by_expert_panel, 3 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
BRCA1	NM_007294.4	c.3648dupA	p.Ser1217IlefsTer2	frameshift_variant	Exon 10 of 23	ENST00000357654.9	NP_009225.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
BRCA1	ENST00000357654.9	c.3648dupA	p.Ser1217IlefsTer2	frameshift_variant	Exon 10 of 23	1	NM_007294.4	ENSP00000350283.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000398 AC: 1 AN: 251312 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 135814

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000289

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: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461870 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 727240

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000224

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: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:18

Revision: reviewed by expert panel

Submissions by phenotype

Breast-ovarian cancer, familial, susceptibility to, 1 Pathogenic:6

-

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

The BRCA1 p.Ser1217IlefsX2 duplication variant was identified in 2 of 3240 proband chromosomes (frequency: 0.001) from individuals with breast or ovarian cancer (Caux-Moncoutier 2011, Vogel 2007). The variant was also identified in dbSNP (ID: rs80357902) “With Pathogenic allele”, HGMD, the ClinVar database (classified as pathogenic by the Sharing Clinical Reports Project, derived from Myriad reports; classified as pathogenic by GeneDX), the BIC database (3X as a variant with clinical importance; classified as pathogenic), and UMD (6X as a causal variant). The p.Ser1217IlefsX2 deletion/duplication/insertion variant is predicted to cause a frameshift, which alters the protein's amino acid sequence beginning at codon 1217 and leads to a premature stop codon at position 1218. This alteration is then predicted to result in a truncated or absent protein and loss of function. Loss of function variants of the BRCA1 gene are an established mechanism of disease in hereditary breast and ovarian cancer 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. -

Oct 09, 2009

Sharing Clinical Reports Project (SCRP)

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Dec 23, 2003

Breast Cancer Information Core (BIC) (BRCA1)

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Sep 08, 2016

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

Significance: Pathogenic

Review Status: reviewed by expert panel

Collection Method: curation

Variant allele predicted to encode a truncated non-functional protein. -

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

- -

Jan 30, 2024

Baylor Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Hereditary breast ovarian cancer syndrome Pathogenic:5

Mar 19, 2021

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.3648dupA (p.Ser1217IlefsX2) 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 allele was found at a frequency of 4e-06 in 251312 control chromosomes (gnomAD). c.3648dupA has been reported in the literature in multiple individuals affected with Hereditary Breast and Ovarian Cancer Syndrome (example: Peyrat_1998, Vogel_2007, Tonin_1998, Rebbeck_2018). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Nine other ClinVar submitters (evaluation after 2014) including an expert panel (ENIGMA) cite the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -

Jan 31, 2014

Research Molecular Genetics Laboratory, Women's College Hospital, University of Toronto

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: research

- -

Nov 22, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change creates a premature translational stop signal (p.Ser1217Ilefs*2) 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 present in population databases (rs80357902, gnomAD 0.003%). This premature translational stop signal has been observed in individual(s) with breast and/or ovarian cancer (PMID: 10866029, 21120943, 22762150). This variant is also known as 3768insA. ClinVar contains an entry for this variant (Variation ID: 37535). For these reasons, this variant has been classified as Pathogenic. -

May 30, 2016

CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jun 29, 2017

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.Ser1217fs variant in BRCA1 has been reported in 2 individuals with breast and/or ovarian cancer (Peyrat 1998, Risch 2001) and has also been identified in 1/33566 of Latino chromosomes by the Genome Aggregation Database (gnomAD, http:/ /gnomad.broadinstitute.org; dbSNP rs80357902). This variant is predicted to caus e a frameshift, which alters the protein?s amino acid sequence beginning at posi tion 1217 and leads to a premature termination codon 2 amino acids downstream. T his alteration is then predicted to lead to a truncated or absent protein. Heter ozygous loss of function of the BRCA1 gene is an established disease mechanism i n hereditary breast and ovarian cancer (HBOC). In addition, this variant was cla ssified as pathogenic on Sept 8, 2016 by the ClinGen-approved ENIGMA expert pane l (ClinVar SCV000299986.2). In summary, this variant meets criteria to be classi fied as pathogenic for HBOC in an autosomal dominant manner based upon the predi cted impact to the protein and low frequency in controls. -

not provided Pathogenic:3

Dec 06, 2021

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Observed in individuals with personal or family history of breast and/or ovarian cancer and has been suggested to be a French Canadian founder variant (Peyrat 1998, Tonin 1998, Risch 2001, Cavallone 2010, Zhang 2011); Truncating variants in this gene are considered pathogenic by a well-established clinical consortium and/or database; Not observed at significant frequency in large population cohorts (Lek 2016); Also known as 3767dupA; This variant is associated with the following publications: (PMID: 20694749, 10866029, 23364291, 15382066, 11179017, 17826769, 10422801, 11307153, 19383375, 9792861, 16143014, 10782928, 21120943, 11453973, 21324516, 25884701, 16905680, 17917138, 17386038, 30630528, 30720243, 31447099) -

May 01, 2024

Quest Diagnostics Nichols Institute San Juan Capistrano

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The BRCA1 c.3648dup (p.Ser1217Ilefs*2) variant alters the translational reading frame of the BRCA1 mRNA and causes the premature termination of BRCA1 protein synthesis. This variant has been reported in the published literature in in individuals and affected with breast/ovarian cancer (PMID: 9792861 (1998), 11179017 (2001), 17925560 (2007), 21120943 (2011), 21324516 (2011), 22762150 (2012), 30630528 (2019)). This variant has also been identified in an individual with a gynecological cancer (PMID: 37310942 (2023)). The frequency of this variant in the general population, 0.000004 (1/251312 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is consistent with pathogenicity. Based on the available information, this variant is classified as pathogenic. -

May 16, 2019

Mayo Clinic Laboratories, Mayo Clinic

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PVS1, PM2, PP5 -

Hereditary cancer-predisposing syndrome Pathogenic:2

Aug 08, 2022

Color Diagnostics, LLC DBA Color Health

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant inserts 1 nucleotide in exon 10 of the BRCA1 gene, creating a frameshift and premature translation stop signal. This variant is also known as 3768insA in the literature. This variant is expected to result in an absent or non-functional protein product. This variant has been reported in multiple individuals and families affected with breast and/or ovarian cancer (PMID: 9792861, 17148771, 21120943, 21324516). This variant has also been identified in 1/251312 chromosomes 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. -

Dec 01, 2022

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.3648dupA pathogenic mutation, located in coding exon 9 of the BRCA1 gene, results from a duplication of A at nucleotide position 3648, causing a translational frameshift with a predicted alternate stop codon (p.S1217Ifs*2). This mutation has been identified in high risk breast/ovarian cancer families of French, French Canadian, and Hispanic descent (Peyrat JP et al. Eur. J. Cancer Prev. 1998 Feb;7 Suppl 1:S7-12; Vogel KJ et al. J. Clin. Oncol. 2007 Oct;25(29):4635-41; Tonin PN et al. Am. J. Hum. Genet. 1998 Nov;63(5):1341-51; Cavallone L et al. Fam. Cancer 2010 Dec;9(4):507-17; Caux-Moncoutier V et al. Hum. Mutat. 2011 Mar;32(3):325-34; Fernández-Lopez JC et al. Hum. Genomics 2019 01;13(1):3), as well as in unselected individuals diagnosed with ovarian cancer (Risch HA et al. Am. J. Hum. Genet. 2001 Mar;68(3):700-10; Zhang S et al. Gynecol. Oncol. 2011 May;121(2):353-7). This alteration was also identified in a large, worldwide study of BRCA1/2 mutation positive families (Rebbeck et al. Hum. Mutat. 2018 05;39(5):593-620). Of note, this alteration is also designated as 3767insA and 3768insA 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. -

Breast and/or ovarian cancer Pathogenic:1

Aug 18, 2021

CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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

Apr 10, 2022

Fulgent Genetics, Fulgent Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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: rs80357902; hg19: chr17-41243899;