chr17-43124044-A-C

Position:

• chr17-43124044-A-C

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM1 PM2 PM5 PP3_Moderate PP5_Very_Strong

The NM_007294.4(BRCA1):​c.53T>G​(p.Met18Arg) variant causes a missense 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 Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. M18T) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: BRCA1 NM_007294.4 missense
• Clinical Significance: Likely pathogenic criteria provided, multiple submitters, no conflicts P:2 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 16 ACMG points.

• PM1: In a helix (size 13) in uniprot entity BRCA1_HUMAN there are 4 pathogenic changes around while only 1 benign (80%) in NM_007294.4
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr17-43124044-A-G is described in Lovd as [Pathogenic].
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.897
• PP5: Variant 17-43124044-A-C is Pathogenic according to our data. Variant chr17-43124044-A-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 531241.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
BRCA1	NM_007294.4	c.53T>G	p.Met18Arg	missense_variant	2/23	ENST00000357654.9	NP_009225.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
BRCA1	ENST00000357654.9	c.53T>G	p.Met18Arg	missense_variant	2/23	1	NM_007294.4	ENSP00000350283	P4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:2 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

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

not provided, no classification provided	in vitro	Brotman Baty Institute, University of Washington	-	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Molecular Endocrinology Laboratory, Christian Medical College	-	- -

Hereditary breast ovarian cancer syndrome Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Oct 03, 2023

This sequence change replaces methionine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 18 of the BRCA1 protein (p.Met18Arg). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with breast cancer and/or ovarian cancer (Invitae). ClinVar contains an entry for this variant (Variation ID: 531241). Advanced modeling performed at Invitae incorporating data from internal and/or published experimental studies (PMID: 30209399) indicates that this missense variant is expected to disrupt BRCA1 function. Experimental studies have shown that this missense change affects BRCA1 function (PMID: 30209399). This variant disrupts the p.Met18 amino acid residue in BRCA1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 17924331, 21922593, 21990134, 23161852, 23867111). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.96
BayesDel_addAF	Pathogenic	0.39	D
BayesDel_noAF	Pathogenic	0.32
CADD	Pathogenic	26
DANN	Uncertain	0.99
DEOGEN2	Benign	0.25	.;T;.;.;.;T;.;T;T;.;T;T;.;T
Eigen	Uncertain	0.42
Eigen_PC	Uncertain	0.38
FATHMM_MKL	Uncertain	0.86	D
LIST_S2	Uncertain	0.95	D;D;D;D;D;D;D;D;D;D;D;D;D;D
M_CAP	Pathogenic	0.63	D
MetaRNN	Pathogenic	0.90	D;D;D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Uncertain	0.30	D
MutationAssessor	Benign	1.0	L;L;L;L;L;.;.;.;.;.;.;.;.;.
MutationTaster	Benign	1.0	D;D;D;D;D;D;D;D;D;D;N;N;N;N
PrimateAI	Uncertain	0.75	T
PROVEAN	Benign	-0.78	N;N;N;N;N;D;N;.;N;N;N;D;D;.
REVEL	Pathogenic	0.81
Sift	Uncertain	0.0010	D;D;D;D;D;D;D;.;D;D;D;D;T;.
Sift4G	Uncertain	0.0060	D;D;D;D;D;.;D;.;D;.;D;.;.;.
Polyphen		0.97, 0.98, 1.0	.;D;.;.;D;.;D;.;.;.;.;.;.;.
Vest4		0.91
MutPred		0.79		Loss of stability (P = 0.0169);Loss of stability (P = 0.0169);Loss of stability (P = 0.0169);Loss of stability (P = 0.0169);Loss of stability (P = 0.0169);Loss of stability (P = 0.0169);Loss of stability (P = 0.0169);Loss of stability (P = 0.0169);Loss of stability (P = 0.0169);Loss of stability (P = 0.0169);Loss of stability (P = 0.0169);Loss of stability (P = 0.0169);Loss of stability (P = 0.0169);Loss of stability (P = 0.0169);
MVP		0.94
MPC		0.52
ClinPred		0.77	D
GERP RS		3.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.95
gMVP		0.88

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.17		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: rs80356929; hg19: chr17-41276061;