rs80357868

Variant names:

• chr17-43091771-TAGAC-T
• rs80357868
• NM_007294.4:c.3756_3759delGTCT

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PVS1 PP5_Very_Strong

The NM_007294.4(BRCA1):​c.3756_3759delGTCT​(p.Ser1253ArgfsTer10) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000143 in 1,614,000 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: 𝑓 0.000013 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000014 (0 hom.)
• Consequence: BRCA1 NM_007294.4 frameshift
• Clinical Significance: Pathogenic reviewed by expert panel P:54
• Conservation: PhyloP100: 3.02

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 16 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PP5: Variant 17-43091771-TAGAC-T is Pathogenic according to our data. Variant chr17-43091771-TAGAC-T is described in ClinVar as [Pathogenic]. Clinvar id is 17673.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr17-43091771-TAGAC-T is described in Lovd as [Pathogenic]. Variant chr17-43091771-TAGAC-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
BRCA1	NM_007294.4	c.3756_3759delGTCT	p.Ser1253ArgfsTer10	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.3756_3759delGTCT	p.Ser1253ArgfsTer10	frameshift_variant	Exon 10 of 23	1	NM_007294.4	ENSP00000350283.3

Frequencies

GnomAD3 genomes AF: 0.0000131 AC: 2 AN: 152210 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000239 AC: 6 AN: 251272 Hom.: 0 AF XY: 0.0000147 AC XY: 2 AN XY: 135786

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

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: 0.0000440

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.0000144 AC: 21 AN: 1461790 Hom.: 0 AF XY: 0.0000165 AC XY: 12 AN XY: 727208

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: 0.0000180

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome AF: 0.0000131 AC: 2 AN: 152210 Hom.: 0 Cov.: 32 AF XY: 0.0000134 AC XY: 1 AN XY: 74358

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000294

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000434 Hom.: 0

Bravo AF: 0.0000113

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:54

Revision: reviewed by expert panel

Submissions by phenotype

Breast-ovarian cancer, familial, susceptibility to, 1 Pathogenic:23

Nov 19, 2013

Sharing Clinical Reports Project (SCRP)

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Mar 29, 2024

Baylor Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Dec 01, 1994

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

May 29, 2002

Breast Cancer Information Core (BIC) (BRCA1)

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

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

- -

-

Neuberg Centre For Genomic Medicine, NCGM

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jun 25, 2019

HudsonAlpha Institute for Biotechnology, HudsonAlpha Institute for Biotechnology

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

- -

-

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Apr 22, 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. -

Dec 11, 2023

All of Us Research Program, National Institutes of Health

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant deletes 4 nucleotides in exon 10 of the BRCA1 gene, creating a frameshift and premature translation stop signal. This variant is also known as 3875_3878delGTCT, 3875del4, 3875delGTCT in the literature based on the BIC nomenclature. This variant is expected to result in an absent or non-functional protein product. This variant has been observed in multiple individuals affected with breast and ovarian cancer (PMID: 16168118, 21324516, 21989927, 22711857, 23633455) and pancreatic cancer (PMID: 21989927), and has been described as a common cause of hereditary breast-ovarian cancer in the French-Canadian population (PMID: 23199084). A breast cancer case-control meta-analysis reported this variant in 15/60466 cases and 2/53461 unaffected individuals with OR=6.633 (95%CI 1.517 to 29.005) (PMID: 33471991; Leiden Open Variation Database DB-ID BRCA1_000278). This variant has been identified in 6/251272 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. -

May 09, 2022

Institute of Human Genetics, University of Leipzig Medical Center

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

_x000D_ Criteria applied: PVS1, PS4 -

Nov 01, 2017

Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.3756_3759delGTCT (p.Ser1253Argfs*10) frame shift variant is predicted to yield loss of function transcripts/proteins of BRCA1 gene, which is one of mechanisms causing BRCA1 defect related cancers. This variant is extremely rare in general population (4 in 246010 by gnomad) and observed in multiple breast/ovarian cancer patients (PMID:78944991, 12947551, 21324516, 23633455, 24504028). It has been also observed in other clinical labs and reported as pathogenic. Based on the above evidences, we interpret this variant as pathogenic. -

May 03, 2020

Genomic Research Center, Shahid Beheshti University of Medical Sciences

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

May 27, 2024

Department of Clinical Genetics, Copenhagen University Hospital, Rigshospitalet

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PVS1; PM5_PTC_Strong -

Feb 11, 2015

Institute of Human Genetics, Medical University Innsbruck

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Mar 02, 2020

BRCAlab, Lund University

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Feb 25, 2020

Genetics and Molecular Pathology, SA Pathology

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The BRCA1 c.3756_3759delGTCT variant is classified as Pathogenic (PVS1, PM2, PP5_Moderate) This BRCA1 c.3756_3759delGTCT variant is predicted to cause a shift in the reading frame at codon 1253, introducing a premature termination codon (PVS1). The variant has been reported in dbSNP (rs80357868) and has been reported as Pathogenic by other diagnostic laboratories (ClinVar Variation ID: 17673). It has not been reported in HGMD. -

Sep 21, 2015

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Apr 02, 2020

Department of Molecular Diagnostics, Institute of Oncology Ljubljana

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 01, 2017

Genologica Medica

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Feb 10, 2015

Department of Medical Genetics, Oslo University Hospital

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 07, 2022

MGZ Medical Genetics Center

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Nov 24, 2014

Counsyl

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: literature only

- -

not provided Pathogenic:11

Oct 17, 2017

Clinical Genetics and Genomics, Karolinska University Hospital

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Aug 01, 2023

CeGaT Center for Human Genetics Tuebingen

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

BRCA1: PVS1, PM2 -

Mar 04, 2025

Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

May 27, 2022

Clinical Genetics Laboratory, Skane University Hospital Lund

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jul 08, 2024

Mayo Clinic Laboratories, Mayo Clinic

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PM5_strong, PVS1 -

Dec 06, 2019

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; Truncating variants in this gene are considered pathogenic by a well-established clinical consortium and/or database; Not observed at a significant frequency in large population cohorts (Lek 2016); This variant is associated with the following publications: (PMID: 21324516, 23621881, 24504028, 27533253, 29310832, 23199084, 31447099, 12947551, 7894491, 23633455, 22711857, 21989927, 27003155, 26779294, 22864640, 25085752, 27356891, 27836010, 27225819, 26843898, 27157322, 27383479, 27062684, 29339979, 28724667, 28423363, 28176296, 30702160, 30720243, 30535581, 31090900, 31159747, 30078507, 30128899, 30103829, 30322717, 26681312, 30093976, 30972954, 31472684, 32388397) -

Nov 03, 2021

Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 09, 2024

Revvity Omics, Revvity

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Oct 23, 2020

Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jun 08, 2023

Quest Diagnostics Nichols Institute San Juan Capistrano

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The BRCA1 c.3756_3759del (p.Ser1253Argfs*10) variant has been reported in the published literature in individuals with breast cancer (PMID: 33646313 (2021), 33471991 (2021), 29339979 (2018), 11183185 (2000), 8531967 (1996)), ovarian cancer (PMID: 33287145 (2020), 30078507 (2018), 21324516 (2011)), and pancreatic cancer (PMID: 21989927 (2012)). This variant has also been described as a French founder mutation (PMID: 23199084 (2010)). The frequency of this variant in the general population, 0.000044 (5/113572 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is consistent with pathogenicity. Based on the available information, this variant is classified as pathogenic. -

-

Clinical Genetics Laboratory, Department of Pathology, Netherlands Cancer Institute

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Hereditary breast ovarian cancer syndrome Pathogenic:6

Apr 22, 2016

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

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: The BRCA1 c.3756_3759delGTCT variant results in a premature termination codon, predicted to cause a truncated or absent BRCA1 protein due to nonsense mediated decay, which are a commonly known mechanism for disease. Truncations downstream of this position have been classified as pathogenic by our laboratory (e.g. p.Gln1756fs). Mutation Taster predicts a damaging outcome for this variant. This variant was found in 3/121438 control chromosomes at a frequency of 0.0000247, which does not exceed maximal expected frequency of a pathogenic BRCA1 allele (0.0010005). The variant has been cited in multiple HBOC patients in the literature. In addition, multiple clinical laboratories/reputable databases classified this variant as pathogenic. Taken together, this variant was classified as pathogenic. -

-

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

The p.Ser1253ArgfsX10 variant has been identified in 17 out of 6280 proband chromosomes (frequency 0.003) in individuals with breast and ovarian cancer phenotype, but not found in 200 control chromosomes included in these studies (Turner 1999, Langston 1996, Castilla 1994, Zhang 2011, Gaj 2012). It is also listed in dbSNP database presented “with untested allele” (ID#: rs80357868) while no frequency information is provided; however, this variant has been listed 27X in the UMD and 123X in the BIC database as a clinically significant mutation. The p.Ser1253ArgfsX10 variant is predicted to cause a frameshift, which alters the protein's amino acid sequence beginning at codon 1253 and leads to a premature stop codon 10 codons downstream. This alteration is then predicted to lead to a truncated or absent BRCA1 protein. Loss of function of the BRCA1 gene is an established disease mechanism in familial breast and ovarian cancer patients. In summary, based on the above information, this variant is 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

- -

Jan 29, 2025

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.Ser1253Argfs*10) 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 (rs80357868, gnomAD 0.003%). This premature translational stop signal has been observed in individual(s) with breast cancer, ovarian cancer, and/or pancreatic cancer (PMID: 7894491, 21324516, 21989927, 23633455). This variant is also known as 3875del4. ClinVar contains an entry for this variant (Variation ID: 17673). For these reasons, this variant has been classified as Pathogenic. -

May 03, 2020

Genomic Research Center, Shahid Beheshti University of Medical Sciences

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Apr 08, 2019

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.Ser12353ArgfsX10 variant in BRCA1 has been reported in >100 individuals with breast and/or ovarian cancer (George 2013, Ghiorzo 2012, Meindl 2002, Pohlreich 2005, Sun 2017, Susswein 2015, Zhang 2011, Breast Cancer Information Core (BIC) ). In addition, this variant was classified as Pathogenic on April 22, 2016 by the ClinGen-approved ENIGMA expert panel (ClinVar VCV000017673.2). This variant has been identified in 0.004% (5/113572) of European chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org). This variant is predicted to cause a frameshift, which alters the protein’s amino acid sequence beginning at position 1253 and leads to a premature termination codon 10 amino acids downstream. This alteration is then predicted to lead to a truncated or absent protein. Heterozygous loss of function of the BRCA1 gene is an established disease mechanism in hereditary breast and ovarian cancer syndrome. In summary, this variant meets criteria to be classified as pathogenic for hereditary breast and ovarian cancer in an autosomal dominant manner. ACMG/AMP Criteria applied: PVS1, PS4. -

Familial cancer of breast Pathogenic:4

-

Center for Precision Medicine, Meizhou People's Hospital

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

-

Bioscientia Institut fuer Medizinische Diagnostik GmbH, Sonic Healthcare

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Jun 24, 2024

Institute of Human Genetics, University of Leipzig Medical Center

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Criteria applied: PVS1, PM5_PTC_STR -

Jan 01, 2020

GeneKor MSA

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change deletes 4 nucleotide from exon 11 of the BRCA1 mRNA (c.3756_3759delGTCT), causing a frameshift after codon 1253 and the creation of a premature translation stop signal 10 amino acid residues later- p.(Ser1253Argfs*10). This is expected to result in an absent or disrupted protein product. Truncating variants in BRCA1 are known to be pathogenic. This variant has been reported in the literature in individuals with inherited breast and/or ovarian cancer, and prostate cancer (PMID: 7894491, 21324516). This variant is also as 3875del4 in the literature.This mutation has been described in the mutation database ClinVar (Variation ID:17673). -

Breast and/or ovarian cancer Pathogenic:3

Jun 11, 2019

CZECANCA consortium

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

May 19, 2015

Foulkes Cancer Genetics LDI, Lady Davis Institute for Medical Research

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

May 17, 2023

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

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Hereditary cancer-predisposing syndrome Pathogenic:3

Oct 18, 2021

Sema4, Sema4

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: curation

- -

Apr 11, 2022

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.3756_3759delGTCT pathogenic mutation, located in coding exon 9 of the BRCA1 gene, results from a deletion of 4 nucleotides at nucleotide positions 3756 to 3759, causing a translational frameshift with a predicted alternate stop codon (p.S1253Rfs*10). This recurrent mutation has been detected in multiple hereditary breast and ovarian cancer (HBOC) syndrome families globally (Castilla LH et al. Nat. Genet. 1994 Dec;8:387-91; Zhang S et al. Gynecol. Oncol. 2011 May;121:353-7; Tedaldi G et al. Oncotarget. 2017 Jul;8:47064-47075; Sun J et al. Clin. Cancer Res. 2017 Oct;23:6113-6119; Heramb C et al. Hered. Cancer Clin. Pract. 2018 Jan;16:3; Bhaskaran SP et al. Int. J. Cancer. 2019 Jan;[Epub ahead of print]). Of note, this alteration is also designated as 3875del4 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. -

Sep 06, 2023

Color Diagnostics, LLC DBA Color Health

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant deletes 4 nucleotides in exon 10 of the BRCA1 gene, creating a frameshift and premature translation stop signal. This variant is also known as 3875_3878delGTCT, 3875del4, 3875delGTCT in the literature based on the BIC nomenclature. This variant is expected to result in an absent or non-functional protein product. This variant has been observed in multiple individuals affected with breast and ovarian cancer (PMID: 16168118, 21324516, 21989927, 22711857, 23633455) and pancreatic cancer (PMID: 21989927), and has been described as a common cause of hereditary breast-ovarian cancer in the French-Canadian population (PMID: 23199084). A breast cancer case-control meta-analysis reported this variant in 15/60466 cases and 2/53461 unaffected individuals with OR=6.633 (95%CI 1.517 to 29.005) (PMID: 33471991; Leiden Open Variation Database DB-ID BRCA1_000278). This variant has been identified in 6/251272 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. -

BRCA1-related disorder Pathogenic:2

Aug 27, 2024

Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This frameshifting variant in exon 10 of 24 is predicted to result in loss of normal protein function through either protein truncation or nonsense-mediated mRNA decay. Loss-of-function variation in BRCA1 is an established mechanism of disease (PMID: 20301425). This variant has been previously reported in individuals with breast and ovarian cancer (PMID: 36292577, 35918668, 33646313, 33287145, 32885271, 32388397, 32341426, 30972954). The c.3756_3759del (p.Ser1253ArgfsTer10) variant is present in the latest version of the gnomAD population database at an allele frequency of 0.001% (23/1614000). Based on the available evidence, c.3756_3759del (p.Ser1253ArgfsTer10) is classified as Pathogenic. -

Mar 06, 2024

PreventionGenetics, part of Exact Sciences

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

The BRCA1 c.3756_3759delGTCT variant is predicted to result in a frameshift and premature protein termination (p.Ser1253Argfs*10). This variant has been reported in individuals with breast and ovarian cancer (Carter et al. 2018. PubMed ID: 30322717, supplementary table 1; Table S1, Chan et al. 2018. PubMed ID: 30093976; George et al. 2013. PubMed ID: 23633455). This variant is reported in 0.0044% of alleles in individuals of European (Non-Finnish) descent in gnomAD. This variant is listed in ClinVar as pathogenic (https://www.ncbi.nlm.nih.gov/clinvar/variation/17673/). Frameshift variants in BRCA1 are expected to be pathogenic. This variant is interpreted as pathogenic. -

Malignant tumor of breast Pathogenic:1

-

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

The p.Ser1253ArgfsX10 variant has been identified in 17 out of 6280 proband chromosomes (frequency 0.003) in individuals with breast and ovarian cancer phenotype, but not found in 200 control chromosomes included in these studies (Turner 1999, Langston 1996, Castilla 1994, Zhang 2011, Gaj 2012). It is also listed in dbSNP database presented ?with untested allele? (ID#: rs80357868) while no frequency information is provided; however, this variant has been listed 27X in the UMD and 123X in the BIC database as a clinically significant mutation. The p.Ser1253ArgfsX10 variant is predicted to cause a frameshift, which alters the protein's amino acid sequence beginning at codon 1253 and leads to a premature stop codon 10 codons downstream. This alteration is then predicted to lead to a truncated or absent BRCA1 protein. Loss of function of the BRCA1 gene is an established disease mechanism in familial breast and ovarian cancer patients. In summary, based on the above information, this variant is classified as pathogenic. -

Ovarian neoplasm Pathogenic:1

Dec 01, 2018

German Consortium for Hereditary Breast and Ovarian Cancer, University Hospital Cologne

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: research

- -

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: rs80357868; hg19: chr17-41243788;