chr17-43124096-T-C

Variant names:

• chr17-43124096-T-C
• rs80357287
• NM_007294.4:c.1A>G

Variant summary

Our verdict is Pathogenic. Variant got 20 ACMG points: 20P and 0B. PVS1 PS1_Moderate PM2 PP5_Very_Strong

The NM_007294.4(BRCA1):​c.1A>G​(p.Met1?) variant causes a start lost change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000206 in 1,459,096 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 Likely pathogenic (★★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: BRCA1 NM_007294.4 start_lost
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:22 O:1
• Conservation: PhyloP100: 2.13

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 20 ACMG points.

• PVS1: Start lost variant, next in-frame start position is after 19 pathogenic variants. Next in-frame start position is after 18 codons. Genomic position: 43124045. Lost 0.009 part of the original CDS.
• PS1: Another start lost variant in NM_007294.4 (BRCA1) was described as [Pathogenic] in Lovd
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 17-43124096-T-C is Pathogenic according to our data. Variant chr17-43124096-T-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 54432.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-43124096-T-C is described in Lovd as [Pathogenic]. Variant chr17-43124096-T-C is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
BRCA1	NM_007294.4	c.1A>G	p.Met1?	start_lost	Exon 2 of 23	ENST00000357654.9	NP_009225.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
BRCA1	ENST00000357654.9	c.1A>G	p.Met1?	start_lost	Exon 2 of 23	1	NM_007294.4	ENSP00000350283.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000206 AC: 3 AN: 1459096 Hom.: 0 Cov.: 29 AF XY: 0.00000275 AC XY: 2 AN XY: 726090

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: 0.00000180

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:22 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Breast-ovarian cancer, familial, susceptibility to, 1 Pathogenic:7 Other:1

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

- -

Nov 03, 2014

Michigan Medical Genetics Laboratories, University of Michigan

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jul 01, 2015

Department of Medical Genetics, Oslo University Hospital

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Feb 20, 2004

Breast Cancer Information Core (BIC) (BRCA1)

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

-

Brotman Baty Institute, University of Washington

Significance: not provided

Review Status: no classification provided

Collection Method: in vitro

- -

Mar 02, 2020

BRCAlab, Lund University

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Oct 02, 2023

All of Us Research Program, National Institutes of Health

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant disrupts the translation initiation codon of the BRCA1 protein and is expected to result in an absent or non-functional protein product. A functional study reports that this variant impacts BRCA1 function in a haploid human cell proliferation assay (PMID: 30209399). This variant has been reported in at least seven individuals affected with breast cancer (PMID: 12827452, 16912212, 24884479, 33471991; Leiden Open Variation Database DB-ID BRCA1_001519), ovarian cancer (PMID: 24504028) and fallopian tube cancer (PMID: 22006311). A multifactorial analysis reported segregation and tumor pathology likelihood ratios for pathogenicity at 1.2716 and 2.2261, respectively (PMID: 31131967). This variant has not been identified 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. -

Feb 01, 2010

Sharing Clinical Reports Project (SCRP)

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Hereditary breast ovarian cancer syndrome Pathogenic:5

Dec 12, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change affects the initiator methionine of the BRCA1 mRNA. The next in-frame methionine is located at codon 18. This variant is not present in population databases (gnomAD no frequency). Disruption of the initiator codon has been observed in individual(s) with breast and/or ovarian cancer (PMID: 11802209, 12827452, 21120943, 22006311, 24504028). This variant is also known as Met1Val and 120A>G. ClinVar contains an entry for this variant (Variation ID: 54432). Algorithms developed to predict the effect of variants on gene product structure and function are not available or were not evaluated for this variant. Experimental studies have shown that disruption of the initiator codon affects BRCA1 function (PMID: 21922593, 30209399). For these reasons, this variant has been classified as Pathogenic. -

Oct 14, 2019

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.Met1Val variant in BRCA1 has been reported in at least 11 individuals with a personal or family history of hereditary breast and/or ovarian cancer (HBOC; Meindl 2002, Walsh 2011, Cunningham 2014, BIC database). It was absent from large population studies. This variant has also been reported in ClinVar (Variation ID: 54432). This variant affects the translation initiation start codon (ATG) and is therefore predicted to disrupt translation although a variety of outcomes (no protein synthesis or the activation of an upstream translation initiation codon) are possible. In vitro functional studies support an impact to the protein (Findlay 2018). In summary, although additional studies are required to fully establish its clinical significance, this variant meets criteria to be classified as likely pathogenic. ACMG/AMP Criteria applied: PM2, PS3_Moderate, PS4_Moderate. -

Jul 02, 2018

Mendelics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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

- -

Oct 28, 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.1A>G alters the initiation codon (therefore the predicted protein level name is p.Met1Val) and is expected to result either in absence of the protein or truncation of the encoded protein due to translation initiation at a downstream codon. Three of four in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 250886 control chromosomes (gnomAD). c.1A>G has been reported in the literature in multiple families and individuals affected with Hereditary Breast and Ovarian Cancer (e.g. Meindl_2002, Rostagno_2003, Walsh_2011, Silva_2014). These data indicate that the variant is very likely to be associated with disease. Six clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar (evaluation after 2014) and cited the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -

not provided Pathogenic:4

Jan 05, 2021

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Initiation codon variant in a gene for which loss-of-function is a known mechanism of disease; Published functional studies demonstrate a damaging effect: variant classified as non-functional based on a saturation genome editing (SGE) assay measuring cell survival, and demonstrated increased sensitivity to irradiation (Baert 2016, Findlay 2018); Observed in individuals with a personal or family history consistent with pathogenic variants in this gene (Meindl 2002, Rostagno 2003, Walsh 2011, Cunningham 2014, Silva 2014, Heramb 2018); Not observed in large population cohorts (Lek 2016); Also known as 120A>G; This variant is associated with the following publications: (PMID: 24728189, 24448499, 20180971, 12827452, 22006311, 28324225, 29116469, 31131967, 24504028, 11802209, 21709188, 24884479, 27184744, 29339979, 30209399, 29446198, 32341426, 33087888) -

Aug 11, 2023

Quest Diagnostics Nichols Institute San Juan Capistrano

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The BRCA1 c.1A>G variant disrupts the translation initiation codon of the BRCA1 mRNA and is predicted to interfere with BRCA1 protein synthesis. This variant has been reported in the published literature in individuals with a personal or family history of breast and/or ovarian cancer (PMIDs: 35578052 (2022), 35264596 (2022), 33471991 (2021), 35918668 (2022), 32341426 (2020), 28888541 (2017), 24884479 (2014), 24504028 (2014), 22006311 (2011), 12827452 (2003), 11802209 (2002)). Experimental studies report this variant causes loss of BRCA1 protein function and impacts cell viability (PMIDs: 33087888 (2021), 31131967 (2019), 30209399 (2018)). This variant has not been reported in large, multi-ethnic general populations (Genome Aggregation Database, http://gnomad.broadinstitute.org). Based on the available information, this variant is classified as pathogenic. -

Sep 04, 2014

Eurofins Ntd Llc (ga)

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Oct 01, 2022

CeGaT Center for Human Genetics Tuebingen

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Hereditary cancer-predisposing syndrome Pathogenic:2

Jun 13, 2022

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.M1? pathogenic mutation (also known as c.1A>G), located in coding exon 1 of the BRCA1 gene, results from an A to G substitution at nucleotide position 1. This alters the methionine residue at the initiation codon (ATG). This pathogenic mutation has been described in numerous breast and ovarian cancer families (Meindl A et al. Int. J. Cancer. 2002 Feb;97(4):472-80; Norquist B et al. J. Clin. Oncol. 2011 Aug;29(22):3008-15; Walsh T et al. Proc. Natl. Acad. Sci. U.S.A. 2011 Nov;108(44):18032-7; Cunningham JM et al. Sci. Rep. 2014 Feb;4:4026; Rebbeck TR et al. Hum Mutat. 2018 May;39(5):593-620). This alteration is predicted to result in the loss of the first 17 amino acids of BRCA1. These RING domain residues comprise a significant portion of the N-helix of the four helix bundle that is crucial for BARD1/BRCA1 dimerization which, in turn, is responsible for their mutual stability, appropriate nuclear localization, and ubiquitin ligase activity (Brzovic PS et al. Nat. Struct. Biol. 2001 Oct;8(10): 833-7; Brzovic PS et al. J. Biol. Chem. 2001 Nov;276(44):41399-406; Brzovic PS et al. Proc. Natl. Acad. Sci. U.S.A. 2003 May;100(10):5646-51). One functional study found that this nucleotide substitution is deleterious in a high throughput genome editing haploid cell survival assay (Findlay GM et al. Nature. 2018 Oct;562(7726):217-222). Of note, this alteration is also designated as 120A>G and M1V in published literature. In addition to the clinical data presented in the literature, sequence variations that modify the initiation codon are expected to result in either loss of translation initiation, N-terminal truncation, or cause a shift in the mRNA reading frame. Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. -

Aug 14, 2023

Color Diagnostics, LLC DBA Color Health

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant disrupts the translation initiation codon of the BRCA1 protein and is expected to result in an absent or non-functional protein product. A functional study reports that this variant impacts BRCA1 function in a haploid human cell proliferation assay (PMID: 30209399). This variant has been reported in at least seven individuals affected with breast cancer (PMID: 12827452, 16912212, 24884479, 33471991; Leiden Open Variation Database DB-ID BRCA1_001519), ovarian cancer (PMID: 24504028) and fallopian tube cancer (PMID: 22006311). A multifactorial analysis reported segregation and tumor pathology likelihood ratios for pathogenicity at 1.2716 and 2.2261, respectively (PMID: 31131967). This variant has not been identified 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. -

Inherited breast cancer and ovarian cancer Pathogenic:1

Apr 09, 2025

NHS Central & South Genomic Laboratory Hub

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Breast neoplasm Pathogenic:1

-

A.C.Camargo Cancer Center / LGBM, A.C.Camargo Cancer Center

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

- -

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 BRCA1 p.Met1? variant was identified in 2 of 882 proband chromosomes (frequency: 0.00227) from individuals or families with breast cancer (Palmero_2018_PMID:29907814). The p.Met? variant has been reported in multiple families with breast and ovarian cancer (Meindl 2002, Rostagno 2003, Walsh 2011, Cunningham 2014, Silva 2014, Heramb 2018). The variant was identified in dbSNP (ID: rs80357287) as Pathogenic, ClinVar (Pathogenic, 2 stars. Classified as pathogenic 12x), LOVD 3.0 (25 entries, 19x pathogenic, 6x VUS), ARUP Laboratories (5-definitely pathogenic), databases. The variant was not identified in the following control databases: the 1000 Genomes Project, the NHLBI GO Exome Sequencing Project, or the Genome Aggregation Database (March 6, 2019, v2.1.1). This variant affects the translation initiation start codon (ATG) and is therefore predicted to disrupt translation, however a variety of outcomes (no protein synthesis or the activation of an upstream translation initiation codon) are possible. A homology-directed DNA repair assay suggested the variant results in loss of protein function (Findlay_2018_PMID:30209399). The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. In summary, based on the above information this variant meets our laboratory’s criteria to be classified as pathogenic. -

Familial cancer of breast Pathogenic:1

-

Center for Precision Medicine, Meizhou People's Hospital

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.40	D
BayesDel_noAF	Pathogenic	0.34
CADD	Uncertain	24
DANN	Uncertain	0.98
DEOGEN2	Benign	0.28	.;T;.;.;.;T;.;T;T;.;T;T;.;T
Eigen	Uncertain	0.31
Eigen_PC	Uncertain	0.28
FATHMM_MKL	Uncertain	0.78	D
LIST_S2	Uncertain	0.90	D;D;D;D;D;D;D;D;D;D;D;D;D;D
M_CAP	Pathogenic	0.96	D
MetaRNN	Pathogenic	0.99	D;D;D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Uncertain	0.45	D
PROVEAN	Benign	-0.62	N;N;N;N;N;N;N;.;N;N;N;N;N;.
REVEL	Pathogenic	0.70
Sift	Pathogenic	0.0	D;D;D;D;D;D;D;.;D;D;D;D;D;.
Sift4G	Benign	0.068	T;D;D;T;T;.;D;.;D;.;D;.;.;.
Polyphen		0.92, 0.45, 0.99	.;P;.;.;B;.;D;.;.;.;.;.;.;.
Vest4		0.94
MutPred		1.0		Loss of stability (P = 0.1939);Loss of stability (P = 0.1939);Loss of stability (P = 0.1939);Loss of stability (P = 0.1939);Loss of stability (P = 0.1939);Loss of stability (P = 0.1939);Loss of stability (P = 0.1939);Loss of stability (P = 0.1939);Loss of stability (P = 0.1939);Loss of stability (P = 0.1939);Loss of stability (P = 0.1939);Loss of stability (P = 0.1939);Loss of stability (P = 0.1939);Loss of stability (P = 0.1939);
MVP		0.88
ClinPred		0.99	D
GERP RS		3.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.95
gMVP		0.28

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		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: rs80357287; hg19: chr17-41276113; COSMIC: COSV58798164; COSMIC: COSV58798164;