17-43124044-A-T

Position:

• chr17-43124044-A-T

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PM1 PM2 PM5 PP3_Strong PP5_Very_Strong

The ENST00000357654.9(BRCA1):​c.53T>A​(p.Met18Lys) 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 ENST00000357654.9 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:4 U: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 18 ACMG points.

• PM1: In a hotspot region, there are 9 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 6 benign, 17 uncertain in ENST00000357654.9
• 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 ClinVar as [Pathogenic]. Clinvar id is 37664.Status of the report is reviewed_by_expert_panel, 3 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.961
• PP5: Variant 17-43124044-A-T is Pathogenic according to our data. Variant chr17-43124044-A-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 55559.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>A	p.Met18Lys	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>A	p.Met18Lys	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: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:4 Uncertain:2 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Hereditary breast ovarian cancer syndrome Pathogenic:3

Likely pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Apr 01, 2023	ClinVar contains an entry for this variant (Variation ID: 55559). 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. 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: 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. Experimental studies have shown that this missense change affects BRCA1 function (PMID: 16403807, 18493658, 25823446, 30209399). 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. This missense change has been observed in individual(s) with breast and ovarian cancer (PMID: 11748848, 15024741, 32803532). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces methionine, which is neutral and non-polar, with lysine, which is basic and polar, at codon 18 of the BRCA1 protein (p.Met18Lys). -
Likely pathogenic, criteria provided, single submitter	clinical testing	Breast Center, Key Laboratory of Carcinogenesis and Translational Research	May 01, 2020	- -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	May 08, 2023	Variant summary: BRCA1 c.53T>A (p.Met18Lys) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 251084 control chromosomes (gnomAD). c.53T>A has been reported in the literature in multiple individuals, many of Czech ancestry, affected with Hereditary Breast And Ovarian Cancer Syndrome (e.g. Southey_1999, Machackova_2001, Foretova_2004, Machackova_2019, Wan_2021). These data indicate that the variant is likely associated with disease. Co-occurrences with other pathogenic variants (BRCA2 c.9154C>T , p.Arg3052Trp; BRCA2 c.7007G>A, p.Arg2336His) have also been reported, providing supporting evidence for a benign role; however, in both of these cases there was a history of breast/ovarian cancer on both the paternal and maternal sides of the families (Machackova_2019). Multiple functional studies report experimental evidence evaluating an impact on protein function and found that the variant impairs ubiquitin ligase activity (e.g. Morris_2006, Starita_2015) and showed this variant to have non-functional homology directed repair (HDR) activity (Findlay_2018). HDR assays qualify as a recognized gold standard on the basis of updated guidance provided by the ClinGen Sequence Variant Interpretation (SVI) working group. Furthermore, a variant affecting the same amino acid (p.Met18Thr) has been classified as pathogenic, suggesting Met18 is important for BRCA1 function. The following publications have been ascertained in the context of this evaluation (PMID: 30209399, 15024741, 11748848, 31409081, 16403807, 10408690, 25823446, 32803532). Three submitters have provided clinical-significance assessments for this variant to ClinVar after 2014 and all classified the variant as likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -

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

not provided, no classification provided	in vitro	Brotman Baty Institute, University of Washington	-	- -
Uncertain significance, no assertion criteria provided	clinical testing	Breast Cancer Information Core (BIC) (BRCA1)	Sep 27, 2005	- -

Breast and/or ovarian cancer Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

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

Jul 16, 2019

- -

not specified Uncertain:1

Uncertain significance, no assertion criteria provided

research

Research Molecular Genetics Laboratory, Women's College Hospital, University of Toronto

Jan 31, 2014

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.96
BayesDel_addAF	Pathogenic	0.38	D
BayesDel_noAF	Pathogenic	0.31
CADD	Uncertain	25
DANN	Uncertain	0.98
DEOGEN2	Benign	0.34	.;T;.;.;.;T;.;T;T;.;T;T;.;T
Eigen	Uncertain	0.36
Eigen_PC	Uncertain	0.34
FATHMM_MKL	Uncertain	0.85	D
LIST_S2	Uncertain	0.95	D;D;D;D;D;D;D;D;D;D;D;D;D;D
M_CAP	Pathogenic	0.61	D
MetaRNN	Pathogenic	0.96	D;D;D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Uncertain	0.25	D
MutationAssessor	Benign	0.71	N;N;N;N;N;.;.;.;.;.;.;.;.;.
MutationTaster	Benign	1.0	D;D;D;D;D;D;D;D;D;D;N;N;N;N
PrimateAI	Uncertain	0.76	T
PROVEAN	Benign	-0.49	N;N;N;N;N;D;N;.;N;N;N;D;D;.
REVEL	Pathogenic	0.77
Sift	Uncertain	0.0010	D;D;D;D;D;D;D;.;D;T;D;D;T;.
Sift4G	Uncertain	0.0060	D;D;D;D;D;.;D;.;D;.;D;.;.;.
Polyphen		0.91, 0.98, 0.99	.;P;.;.;D;.;D;.;.;.;.;.;.;.
Vest4		0.90
MutPred		0.91		Loss of stability (P = 0.0047);Loss of stability (P = 0.0047);Loss of stability (P = 0.0047);Loss of stability (P = 0.0047);Loss of stability (P = 0.0047);Loss of stability (P = 0.0047);Loss of stability (P = 0.0047);Loss of stability (P = 0.0047);Loss of stability (P = 0.0047);Loss of stability (P = 0.0047);Loss of stability (P = 0.0047);Loss of stability (P = 0.0047);Loss of stability (P = 0.0047);Loss of stability (P = 0.0047);
MVP		0.93
MPC		0.48
ClinPred		0.76	D
GERP RS		3.8
Varity_R		0.95
gMVP		0.86

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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;