rs80357111

chr17-43124095-A-Cchr17-43124095-A-Gchr17-43124095-A-T

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.2T>G(p.Met1?) variant causes a start lost change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: BRCA1 NM_007294.4 start_lost
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:4 O:1
• Conservation: PhyloP100: 4.17

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, no new inframe start found.
• PS1: Another start lost variant in NM_007294.4 (BRCA1) was described as [Pathogenic] in ClinVar as 55072
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 17-43124095-A-C is Pathogenic according to our data. Variant chr17-43124095-A-C is described in ClinVar as [Pathogenic]. Clinvar id is 54746.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-43124095-A-C is described in Lovd as [Pathogenic]. Variant chr17-43124095-A-C is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
BRCA1	NM_007294.4	c.2T>G	p.Met1?	start_lost	2/23	ENST00000357654.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
BRCA1	ENST00000357654.9	c.2T>G	p.Met1?	start_lost	2/23	1	NM_007294.4	P4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 29

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:4 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Hereditary breast ovarian cancer syndrome Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Aug 22, 2020	For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this variant affects BRCA1 protein function (PMID: 30209399, 21922593). Disruption of the initiator codon has been observed in individual(s) with breast and/or ovarian cancer (PMID: 25480878, 28724667, 22006311, 9145677, 11802209). This variant is also known as Met1Arg. ClinVar contains an entry for this variant (Variation ID: 54746). This variant is not present in population databases (ExAC no frequency). This sequence change affects the initiator methionine of the BRCA1 mRNA. The next in-frame methionine is located at codon 18. -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Aug 24, 2020	Variant summary: BRCA1 c.2T>G (p.Met1Arg) alters the initiation codon and is predicted to result either in absence of the protein or truncation of the encoded protein due to translation initiation at a downstream codon. Four of four in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 250886 control chromosomes. c.2T>G has been reported in the literature in individuals affected with Hereditary Breast And Ovarian Cancer Syndrome (example, Sekine_2001, Judkins_2005, Wang_2015, Sun_2017, Bhaskaran_2019, McVeigh_2020). These data indicate that the variant is likely to be associated with disease. At least two publications report experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in loss of function as evaluated by BRCA1-dependent growth of yeast colonies that increases with pathogenic but not neutral mutations (Millot_2011) and cellular fitness in a haploid human cell line whose survival is dependent on intact BRCA1 function (Findlay_2018). One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation and classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -

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

Pathogenic, no assertion criteria provided	clinical testing	Breast Cancer Information Core (BIC) (BRCA1)	Jun 12, 2000	- -
not provided, no classification provided	in vitro	Brotman Baty Institute, University of Washington	-	- -

Hereditary cancer-predisposing syndrome Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Color Diagnostics, LLC DBA Color Health

Apr 29, 2021

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 has reported that this variant impacts BRCA1 function in a haploid human cell proliferation assay (PMID: 30209399). This variant has been observed in at least three individuals affected with breast and ovarian cancer (PMID: 11595708, 25480878, 32008151, 33471991; Leiden Open Variation Database DB-ID BRCA1_002590). A different mutation c.1A>G at codon 1 has been observed in at least 5 individuals affected with breast, ovarian and fallopian tube cancer (PMID: 12827452, 16912212, 22006311, 24504028, 24884479). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.41	D
BayesDel_noAF	Pathogenic	0.35
Cadd	Uncertain	25
Dann	Uncertain	0.98
Eigen	Uncertain	0.37
Eigen_PC	Uncertain	0.32
FATHMM_MKL	Benign	0.76	D
LIST_S2	Uncertain	0.90	D;D;D;D;D;D;D;D;D;D;D;D;D;D
M_CAP	Pathogenic	0.95	D
MetaRNN	Pathogenic	0.99	D;D;D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Uncertain	0.47	D
MutationTaster	Benign	1.0	D;D;D;D;D;D;D;D;D;D;D;D;D;D
PROVEAN	Benign	-0.49	N;N;N;N;N;N;N;.;N;N;N;D;D;.
REVEL	Pathogenic	0.73
Sift	Pathogenic	0.0	D;D;D;D;D;D;D;.;D;D;D;D;D;.
Sift4G	Uncertain	0.0050	D;D;D;D;D;.;D;.;D;.;D;.;.;.
Polyphen		0.99, 0.91, 1.0	.;D;.;.;P;.;D;.;.;.;.;.;.;.
Vest4		0.97
MutPred		1.0		Loss of stability (P = 0.0069);Loss of stability (P = 0.0069);Loss of stability (P = 0.0069);Loss of stability (P = 0.0069);Loss of stability (P = 0.0069);Loss of stability (P = 0.0069);Loss of stability (P = 0.0069);Loss of stability (P = 0.0069);Loss of stability (P = 0.0069);Loss of stability (P = 0.0069);Loss of stability (P = 0.0069);Loss of stability (P = 0.0069);Loss of stability (P = 0.0069);Loss of stability (P = 0.0069);
MVP		0.89
ClinPred		0.96	D
GERP RS		3.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.97
gMVP		0.48

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.14		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: rs80357111; hg19: chr17-41276112;