rs62625308

Variant names:

• chr17-43091924-G-A
• rs62625308
• NM_007294.4:c.3607C>T

Your query was ambiguous. Multiple possible variants found:

• chr17-43091924-G-A
• chr17-43091924-G-C
• chr17-43091924-G-T

Variant summary

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

The NM_007294.4(BRCA1):​c.3607C>T​(p.Arg1203*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000991 in 1,613,832 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★★). Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000010 (0 hom.)
• Consequence: BRCA1 NM_007294.4 stop_gained
• Clinical Significance: Pathogenic reviewed by expert panel P:49 O:1
• Conservation: PhyloP100: 1.16

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 17-43091924-G-A is Pathogenic according to our data. Variant chr17-43091924-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 17671.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr17-43091924-G-A is described in Lovd as [Pathogenic]. Variant chr17-43091924-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
BRCA1	NM_007294.4	c.3607C>T	p.Arg1203*	stop_gained	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.3607C>T	p.Arg1203*	stop_gained	Exon 10 of 23	1	NM_007294.4	ENSP00000350283.3

Frequencies

GnomAD3 genomes AF: 0.00000658 AC: 1 AN: 152042 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000242

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: 0.00

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000120 AC: 3 AN: 251014 Hom.: 0 AF XY: 0.0000221 AC XY: 3 AN XY: 135716

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000546

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000176

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000103 AC: 15 AN: 1461790 Hom.: 0 Cov.: 33 AF XY: 0.0000138 AC XY: 10 AN XY: 727190

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.0000383

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.0000348

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000899

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.00000658 AC: 1 AN: 152042 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 74272

Gnomad4 AFR AF: 0.0000242

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: 0.00

Gnomad4 OTH AF: 0.00

Alfa AF: 0.00000998 Hom.: 0

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.00 AC: 0

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:49 Other:1

Revision: reviewed by expert panel

Submissions by phenotype

Breast-ovarian cancer, familial, susceptibility to, 1 Pathogenic:16 Other:1

Oct 24, 2023

KCCC/NGS Laboratory, Kuwait Cancer Control Center

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change creates a premature translational stop signal (p.Arg1203*) 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 (rs62625308, gnomAD 0.006%). This premature translational stop signal has been observed in individual(s) with breast and ovarian cancer (PMID: 31372034, 31825140, 32832836, 32710294, 7894493, 31447099, 21324516, 25525159, 31159747, 30720243, 28176296, 29446198, 30555256, 30720863, 30702160, 29310832, 28993434, 29470806, 29752822, 29339979, 28961279, 28324225, 27831900, 26848529, 27157322, 26300996, 27848044, 26709275, 25011685, 25722380, 25637381, 22752604, 22006311, 26010302, 25863477, 24010542, 25371446, 26028024). It has also been observed to segregate with disease in related individuals. This variant is also known as 3726C>T. ClinVar contains an entry for this variant (Variation ID: 17671) classified as pathogenic . For these reasons, this variant has been classified as Pathogenic. -

Oct 18, 2012

Sharing Clinical Reports Project (SCRP)

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Dec 01, 1994

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Nov 23, 2023

Baylor Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Dec 16, 2015

Counsyl

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Oct 08, 2018

Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This c.3607C>T (p.Arg1203*) variant in the BRCA1 gene is predicted to introduce a premature translational termination codon. This variant is extremely rare in the general population according to the gnomAD database. It has been reported in multiple unrelated patients with breast cancer or ovary cancer [2PMID: 7894493, 21324516, 22006311, 22752604, 24218521, 24010542].Therefore, the c.3607C>T (p.Arg1203*) variant in the BRCA1 gene is classified as pathogenic. -

Mar 02, 2020

BRCAlab, Lund University

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

- -

-

Breast Cancer Information Core (BIC) (BRCA1)

Significance: not provided

Review Status: no classification provided

Collection Method: clinical testing

- -

Oct 13, 2023

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_STR -

-

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Jan 07, 2022

MGZ Medical Genetics Center

Significance: Pathogenic

Review Status: criteria provided, single submitter

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. -

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 -

Apr 11, 2016

Department of Medical Genetics, Oslo University Hospital

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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 10, 2022

DASA

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.3607C>T;p.(Arg1203*) variant creates a premature translational stop signal in the BRCA1 gene. It is expected to result in an absent or disrupted protein product -PVS1. This sequence change has been observed in affected individual(s) and ClinVar contains an entry for this variant (ClinVar ID: 17671; PMID: 21324516; PMID: 22006311; PMID: 24010542; PMID: 22752604) - PS4. The variant is present at low allele frequencies population databases (rs62625308 – gnomAD 0.0001195%; ABraOM no frequency - http://abraom.ib.usp.br) - PM2_supporting. The variant co-segregated with disease in multiple affected family members (PMID: 7894493) - PP1. In summary, the currently available evidence indicates that the variant is pathogenic -

not provided Pathogenic:9

Dec 02, 2016

Clinical Genetics and Genomics, Karolinska University Hospital

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Apr 12, 2021

Revvity Omics, Revvity

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Mar 04, 2025

Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Aug 18, 2021

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Nonsense 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 several individuals with a personal and/or family history of BRCA1-related cancers (Friedman 1994, Walsh 2011, Zhang 2011, Konstantopoulou 2014, Sung 2017); 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 3726C>T; This variant is associated with the following publications: (PMID: 31372034, 31825140, 32832836, 32710294, 7894493, 31447099, 21324516, 25525159, 31159747, 30720243, 28176296, 29446198, 30555256, 30720863, 30702160, 29310832, 28993434, 29470806, 29752822, 29339979, 28961279, 28324225, 27831900, 26848529, 27157322, 26300996, 27848044, 26709275, 25011685, 25722380, 25637381, 22752604, 22006311, 26010302, 25863477, 24010542, 25371446, 26028024) -

Nov 09, 2023

Quest Diagnostics Nichols Institute San Juan Capistrano

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The BRCA1 c.3607C>T (p.Arg1203*) variant causes the premature termination of BRCA1 protein synthesis. This variant has been reported in the published literature in many individuals with breast and/or ovarian cancer in the published literature (PMIDs: 7894493 (1994), 24218521 (2014), 24010542 (2014), 22752604 (2012), 22006311 (2011), 21553119 (2012), 21324516 (2011), 20104584 (2010), 12655560 (2003), 30702160 (2019), 30555256 (2018), and 28993434 (2018)). The frequency of this variant in the general population, 0.000012 (3/251014 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is consistent with pathogenicity. Based on the available information, this variant is classified as pathogenic. -

May 27, 2022

Clinical Genetics Laboratory, Skane University Hospital Lund

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

The p.Arg1203X variant has been previously reported in the literature in 7 of 12470 individuals with hereditary breast or ovarian cancer (Selected publications: Konstantopoulou 2008, Manguoglu 2003, Borg 2010, Kim 2012). The variant was also reported 22 times in the UMD database ase "causal" and 31 times in the BIC database as "clinically important". The variant was also reported 1 time in the ESP project at low frequency (0.0002) and by dbSNP (ID: rs62625308). This variant leads to a premature stop codon at position 1203, which is predicted to lead to a truncated or absent protein and loss of function. Loss of function variants of the BRCA1 gene are an established mechanism of disease for hereditary breast and ovarian cancer. In summary, based on the above information, this variant is classified as pathogenic. -

-

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Familial cancer of breast Pathogenic:5

Feb 23, 2017

Baylor Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

May 03, 2020

Genomic Research Center, Shahid Beheshti University of Medical Sciences

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Center for Precision Medicine, Meizhou People's Hospital

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Jun 10, 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_STR -

Jan 01, 2020

GeneKor MSA

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change creates a premature translational stop signal at codon 1203, p.(Arg1203*). It is expected to result in an absent or disrupted protein product. Truncating variants in BRCA1 are known to be pathogenic. This particular variant has been reported in the literature in individuals and families affected by breast and ovarian cancer and was shown to segregate with disease in one family (PMID: 21324516, 22006311). This sequence change is also known as 3726C>T in the literature. This mutation has been described in the mutation database ClinVar (Variation ID:17671). -

Hereditary breast ovarian cancer syndrome Pathogenic:5

Apr 24, 2019

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.Arg1203X variant in BRCA1 has been reported in >40 individuals with BRCA1-associated cancers (Friedman 1994, Manguoglu 2003, Walsh 2011, Solano 2012, Kim 2012, Juwle 2012, Couch 2015, Breast Cancer Information Core (BIC) database, Sharing Clinical Reports Project). This variant has been identified in 1/17194 East Asian and 2/111402 European chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs62625308). This nonsense variant leads to a premature termination codon at position 1203, which is predicted to lead to a truncated or absent protein. Heterozygous loss of function of the BRCA1 gene is an established disease mechanism in individuals with hereditary breast and ovarian cancer (HBOC). In addition, this variant was classified as Pathogenic on April 22, 2016 by the ClinGen-approved ENIGMA expert panel (ClinVar SCV000282311.1). In summary, this variant meets criteria to be classified as pathogenic for HBOC in an autosomal dominant manner. ACMG/AMP Criteria applied: PVS1, PM2, PS4. -

Aug 13, 2019

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.3607C>T (p.Arg1203X) 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. Truncations downstream of this position have been classified as pathogenic by our laboratory. The variant allele was found at a frequency of 1.2e-05 in 251014 control chromosomes. c.3607C>T has been reported in the literature in numerous individuals affected with hereditary or early-onset breast and/or ovarian cancer (ie. Friedman_1994, Meindl_2002, Kim_2012, Juwle_2012, Solano_2013, Stavropoulo_2013). 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. 16 clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar (after 2014). All laboratories classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -

Apr 20, 2017

Department of Pathology and Molecular Medicine, Queen's University

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 21, 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.Arg1203*) 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 (rs62625308, gnomAD 0.006%). This premature translational stop signal has been observed in individual(s) with breast and ovarian cancer (PMID: 7894493, 21324516, 22006311, 22752604, 24010542). It has also been observed to segregate with disease in related individuals. This variant is also known as 3726C>T. ClinVar contains an entry for this variant (Variation ID: 17671). For these reasons, this variant has been 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

- -

Breast and/or ovarian cancer Pathogenic:2

Mar 13, 2016

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

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Dec 20, 2013

Foulkes Cancer Genetics LDI, Lady Davis Institute for Medical Research

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Hereditary cancer-predisposing syndrome Pathogenic:2

Nov 27, 2024

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.R1203* pathogenic mutation (also known as c.3607C>T), located in coding exon 9 of the BRCA1 gene, results from a C to T substitution at nucleotide position 3607. This changes the amino acid from an arginine to a stop codon within coding exon 9. This alteration has been reported in multiple families with breast and/or ovarian cancer across various ethnicities (Friedman LS et al. Nat. Genet. 1994 Dec;8:399-404; Zhang S et al. Gynecol. Oncol. 2011 May;121:353-7; Walsh T et al. Proc. Natl. Acad. Sci. U.S.A. 2011 Nov;108:18032-7; Juwle A et al. Med. Oncol. 2012 Dec;29:3272-81; Hirasawa A et al. Jpn. J. Clin. Oncol. 2014 Jan;44:49-56; Konstantopoulou I et al. Clin. Genet. 2014 Jan;85:36-42; Meisel C et al. Arch. Gynecol. Obstet. 2017 May;295:1227-1238). Of note, this alteration is also designated as 3726C>T 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. -

Apr 24, 2023

Color Diagnostics, LLC DBA Color Health

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant changes 1 nucleotide in exon 10 of the BRCA1 gene, creating a premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. This variant has been observed in over ten individuals and families affected with breast and ovarian cancer (PMID: 22006311, 22752604, 22798144, 23961350, 23536787, 24010542, 24218521, 25452441, 28324225, 28993434, 29310832, 29339979, 29470806, 29752822, 30555256, 30720863, 31372034, 33151324, 33471991; Leiden Open Variation Database DB-ID BRCA1_001405) and an individual affected with clear cell renal cell carcinoma (PMID: 33442023). This variant has been identified in 3/251014 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. -

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

Mar 14, 2024

Fulgent Genetics, Fulgent Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Inherited breast cancer and ovarian cancer Pathogenic:1

Sep 06, 2024

Genomics and Molecular Medicine Service, East Genomic Laboratory Hub, NHS Genomic Medicine Service

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PVS1,PM5_Strong -

Breast neoplasm Pathogenic:1

Jun 01, 2014

CSER _CC_NCGL, University of Washington

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: research

- -

Malignant tumor of urinary bladder Pathogenic:1

-

Laboratory of Urology, Hospital Clinic de Barcelona

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: research

- -

Gastric cancer Pathogenic:1

Jul 01, 2021

Laboratory for Genotyping Development, RIKEN

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: research

- -

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

- -

Ovarian cancer Pathogenic:1

Feb 16, 2017

3DMed Clinical Laboratory Inc

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Ovarian carcinoma Pathogenic:1

Sep 11, 2021

Medical Genetics Laboratory, Umraniye Training and Research Hospital, University of Health Sciences

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

BRCA1-related cancer predisposition Pathogenic:1

Jul 29, 2024

All of Us Research Program, National Institutes of Health

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant changes 1 nucleotide in exon 10 of the BRCA1 gene, creating a premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. This variant has been observed in over ten individuals and families affected with breast and ovarian cancer (PMID: 22006311, 22752604, 22798144, 23961350, 23536787, 24010542, 24218521, 25452441, 28324225, 28993434, 29310832, 29339979, 29470806, 29752822, 30555256, 30720863, 31372034, 33151324, 33471991; Leiden Open Variation Database DB-ID BRCA1_001405) and an individual affected with clear cell renal cell carcinoma (PMID: 33442023). This variant has been identified in 3/251014 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:1

May 16, 2023

PreventionGenetics, part of Exact Sciences

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The BRCA1 c.3607C>T variant is predicted to result in premature protein termination (p.Arg1203*). This variant has been widely reported in individuals with hereditary breast and ovarian cancer (see for example, Table 2a, Friedman et al. 1994. PubMed ID: 7894493; Table 1, Meindl et al. 2002. PubMed ID: 11802209). This variant was also reported as germline variant in a patient with renal cell carcinoma (Table S3, Santos et al. 2021. PubMed ID: 33442023). This variant is reported in 0.0055% of alleles in individuals of East Asian descent in gnomAD (http://gnomad.broadinstitute.org/variant/17-41243941-G-A), and it is interpreted as pathogenic in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/17671/). Taken together, this variant is interpreted as pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.25	D
BayesDel_noAF	Pathogenic	0.29
CADD	Pathogenic	34
DANN	Uncertain	0.99
Eigen	Uncertain	0.21
Eigen_PC	Benign	-0.098
FATHMM_MKL	Benign	0.24	N
Vest4		0.85
GERP RS		4.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

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: rs62625308; hg19: chr17-41243941; COSMIC: COSV99066407; COSMIC: COSV99066407;