rs80357475

Variant names:

• chr17-43124094-C-A
• rs80357475
• NM_007294.4:c.3G>T

Your query was ambiguous. Multiple possible variants found:

• chr17-43124094-C-A
• chr17-43124094-C-G
• chr17-43124094-C-T

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM2 PP3_Strong PP5_Very_Strong

The NM_007297.4(BRCA1):​c.-85G>T variant causes a 5 prime UTR premature start codon gain change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000685 in 1,459,880 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 (★★★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: BRCA1 NM_007297.4 5_prime_UTR_premature_start_codon_gain
• Clinical Significance: Pathogenic reviewed by expert panel P:9 O:1
• Conservation: PhyloP100: 3.43

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 14 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.987
• PP5: Variant 17-43124094-C-A is Pathogenic according to our data. Variant chr17-43124094-C-A is described in ClinVar as [Pathogenic]. Clinvar id is 55072.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr17-43124094-C-A is described in Lovd as [Pathogenic]. Variant chr17-43124094-C-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

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

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.85e-7 AC: 1 AN: 1459880 Hom.: 0 Cov.: 29 AF XY: 0.00000138 AC XY: 1 AN XY: 726430

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: 9.01e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:9 Other:1

Revision: reviewed by expert panel

Submissions by phenotype

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

-

Brotman Baty Institute, University of Washington

Significance: not provided

Review Status: no classification provided

Collection Method: in vitro

- -

May 29, 2002

Breast Cancer Information Core (BIC) (BRCA1)

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Jun 18, 2019

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

Significance: Pathogenic

Review Status: reviewed by expert panel

Collection Method: curation

IARC class based on posterior probability from multifactorial likelihood analysis, thresholds for class as per Plon et al. 2008 (PMID: 18951446). Class 5 based on posterior probability = 0.994371 -

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

- -

not provided Pathogenic:2

-

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 the literature in multiple individuals affected by breast cancer (Rebbeck 2018, Lang 2017, Walsh 2011, Gao 2020). The variant was identified in dbSNP (ID: rs80357475), ClinVar (Pathogenic, 3 stars, reviewed by expert panel. Classified as pathogenic by ENIGMA, CIMBA, Fulgent, Ambry, Invitae, Women's College Hospital, BIC, University of Washington), LOVD 3.0 (4 entries, pathogenic), and ARUP Laboratories (Class 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). The p.Met1 residue is conserved in mammals and other organisms, and computational analyses (SIFT, Polyphen2, MT, FATHMM, DANN, MetaLR, Revel) suggest that the variant may impact the protein; however, this information is not predictive enough to assume pathogenicity. This sequence change affects the initiator methionine of the BRCA1 mRNA. While it is expected to result in an absent or disrupted protein product, alternate in-frame methionines downstream of the initiator codon could potentially rescue the translation initiation. A saturation genome editing (SGE) assay for BRCA1 NM_007294.3:c.3G>T produced a function score of -1.9, corresponding to a functional classification of loss of function (Findlay 2018). Another experimental study found that expressing a different variant (p.Met1Arg) in yeast cells, disrupted the initiator methionine and resulted in no protein product (Millot 2011), suggesting that disruption of the initiator methionine affects translation initiation and results in loss of BRCA1 protein function.  In summary, based on the above information this variant meets our laboratory’s criteria to be classified as pathogenic. -

Nov 14, 2023

Quest Diagnostics Nichols Institute San Juan Capistrano

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The BRCA1 c.3G>T 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 affected individuals with breast and/or ovarian cancer (PMIDs: 22006311 (2011), 30702160 (2019), 31825140 (2019)), as well as in breast cancer cases in a large scale breast cancer association study (PMID: 33471991 (2021), see also LOVD (http://databases.lovd.nl/shared/genes/BRCA1)). A functional study showed this variant lost functional activity in a large-scale study using a haploid cell line (PMID: 30209399 (2018)). The variant has also been characterized as being pathogenic in a multifactorial likelihood study (PMID: 31131967 (2019)). 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. -

Hereditary breast ovarian cancer syndrome Pathogenic:2

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

- -

Apr 22, 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: 9145677, 22006311; Invitae). This variant is also known as Met1Ile. ClinVar contains an entry for this variant (Variation ID: 55072). Studies have shown that disruption of the initiator codon alters BRCA1 gene expression (PMID: 21922593). 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

Oct 31, 2018

Fulgent Genetics, Fulgent Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Hereditary cancer-predisposing syndrome Pathogenic:1

Sep 22, 2024

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.M1? pathogenic mutation (also known as c.3G>T) is located in coding exon 1 of the BRCA1 gene and results from a G to T substitution at nucleotide position 3. This alters the methionine residue at the initiation codon (ATG). This alteration has been reported in multiple individuals suspected of hereditary breast and/or ovarian cancer (Shih HA et al. J Clin Oncol. 2002 Feb 15;20(4):994-9; Abkevich V et al. J Med Genet. 2004 Jul;41(7):492-507; Millot GA et al. Hum Mutat. 2012 Nov;33(11):1526-37; Walsh T et al. PNAS. 2011; 108(44):18032-7). This mutation is believed to shift the initiation codon to position 18, producing a BRCA1 protein truncated by 17 amino acids (Couch FJ and Weber BL. Hum Mutat. 1996;8(1):8-18). Well established evidence from the literature on the BRCA1 RING domain indicates the crucial importance of the first 17 amino acids in maintaining the normal structure and function of the protein (Brzovic PS et al Nat Struct Biol. 2001; 8(10): 833-7; Brzovic PS et al J Biol Chem. 2001; 276(44):41399-406; Brzovic PS et al PNAS. 2003;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 10;562(7726):217-222). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). 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 variant is interpreted as a disease-causing mutation. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.40	D
BayesDel_noAF	Pathogenic	0.33
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.28	.;T;.;.;.;T;.;T;T;.;T;T;.;T
Eigen	Uncertain	0.35
Eigen_PC	Uncertain	0.31
FATHMM_MKL	Uncertain	0.77	D
LIST_S2	Uncertain	0.90	D;D;D;D;D;D;D;D;D;D;D;D;D;D
M_CAP	Pathogenic	0.93	D
MetaRNN	Pathogenic	0.99	D;D;D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Uncertain	0.52	D
PROVEAN	Benign	-1.0	N;N;N;N;N;N;N;.;N;N;N;D;N;.
REVEL	Pathogenic	0.70
Sift	Pathogenic	0.0	D;D;D;D;D;D;D;.;D;D;D;D;D;.
Sift4G	Benign	0.48	T;D;D;T;T;.;D;.;D;.;D;.;.;.
Polyphen		0.92, 0.66, 0.99	.;P;.;.;P;.;D;.;.;.;.;.;.;.
Vest4		0.93
MutPred		1.0		Gain of catalytic residue at M1 (P = 0.0314);Gain of catalytic residue at M1 (P = 0.0314);Gain of catalytic residue at M1 (P = 0.0314);Gain of catalytic residue at M1 (P = 0.0314);Gain of catalytic residue at M1 (P = 0.0314);Gain of catalytic residue at M1 (P = 0.0314);Gain of catalytic residue at M1 (P = 0.0314);Gain of catalytic residue at M1 (P = 0.0314);Gain of catalytic residue at M1 (P = 0.0314);Gain of catalytic residue at M1 (P = 0.0314);Gain of catalytic residue at M1 (P = 0.0314);Gain of catalytic residue at M1 (P = 0.0314);Gain of catalytic residue at M1 (P = 0.0314);Gain of catalytic residue at M1 (P = 0.0314);
MVP		0.89
ClinPred		1.0	D
GERP RS		3.8
Varity_R		0.91
gMVP		0.25

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.080		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: rs80357475; hg19: chr17-41276111;