17-43115736-T-G

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 4P and 1B. PM1 PM2 BP6

The NM_007294.4(BRCA1):c.124A>C(p.Ile42Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another nucleotide change resulting in same amino acid change has been previously reported as Uncertain significancein ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. I42K) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: BRCA1 NM_007294.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:1 O:1
• Conservation: PhyloP100: 2.14

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 Uncertain_significance. Variant got 3 ACMG points.

• PM1: In a hotspot region, there are 8 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 2 benign, 17 uncertain in NM_007294.4
• PM2: Very rare variant in population databases, with high coverage
• BP6: Variant 17-43115736-T-G is Benign according to our data. Variant chr17-43115736-T-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 422425.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=2, not_provided=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
BRCA1	NM_007294.4	c.124A>C	p.Ile42Leu	missense_variant	3/23	ENST00000357654.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
BRCA1	ENST00000357654.9	c.124A>C	p.Ile42Leu	missense_variant	3/23	1	NM_007294.4	P4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2 Benign:1 Other:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Oct 05, 2016	This variant is denoted BRCA1 c.124A>C at the cDNA level, p.Ile42Leu (I42L) at the protein level, and results in the change of an Isoleucine to a Leucine (ATA>CTA). Using alternate nomenclature, this variant would be defined as BRCA1 243A>C. This variant was observed in a pediatric patient with T-cell acute lymphoblastic leukemia (Zhang 2015). BRCA1 Ile42Leu was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, suggesting it is not a common benign variant in these populations. Since Isoleucine and Leucine share similar properties, this is considered a conservative amino acid substitution. BRCA1 Ile42Leu occurs at a position that is conserved in mammals and is located within the RING domain as well as the BRD7 and BARD1 binding domains (Narod, 2004, Borg 2010, Harte 2010, Paul 2014). In silico analyses are inconsistent regarding the effect this variant may have on protein structure and function. Based on currently available evidence, it is unclear whether BRCA1 Ile42Leu is a pathogenic or benign variant. We consider it to be a variant of uncertain significance. -
Uncertain significance, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Nov 22, 2019	- -

Hereditary cancer-predisposing syndrome Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

May 28, 2021

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

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

not provided, no classification provided

in vitro

Brotman Baty Institute, University of Washington

-

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.44
BayesDel_addAF	Pathogenic	0.30	D
BayesDel_noAF	Pathogenic	0.19
Cadd	Uncertain	24
Dann	Uncertain	0.99
Eigen	Uncertain	0.38
Eigen_PC	Uncertain	0.47
FATHMM_MKL	Uncertain	0.86	D
LIST_S2	Uncertain	0.90	D;D;D;D;D;D;D;D;D;T;D;D;T
M_CAP	Uncertain	0.17	D
MetaRNN	Uncertain	0.68	D;D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Uncertain	0.64	D
MutationAssessor	Benign	0.10	N;N;N;N;N;.;.;.;.;.;.;.;.
MutationTaster	Benign	0.83	D;D;D;D;D;D;D;D;N;N;N;N;N;N
PrimateAI	Uncertain	0.67	T
PROVEAN	Benign	-0.28	N;N;N;N;N;N;N;.;N;N;N;N;N
REVEL	Uncertain	0.56
Sift	Benign	0.16	T;D;D;T;D;T;D;.;D;D;D;T;T
Sift4G	Benign	0.52	T;D;D;T;T;.;D;.;D;.;D;.;.
Polyphen		0.90, 0.56, 0.94	.;P;.;.;P;.;P;.;.;.;.;.;.
Vest4		0.60
MutPred		0.53		Loss of catalytic residue at I42 (P = 0.1167);Loss of catalytic residue at I42 (P = 0.1167);Loss of catalytic residue at I42 (P = 0.1167);Loss of catalytic residue at I42 (P = 0.1167);Loss of catalytic residue at I42 (P = 0.1167);Loss of catalytic residue at I42 (P = 0.1167);Loss of catalytic residue at I42 (P = 0.1167);Loss of catalytic residue at I42 (P = 0.1167);Loss of catalytic residue at I42 (P = 0.1167);Loss of catalytic residue at I42 (P = 0.1167);Loss of catalytic residue at I42 (P = 0.1167);Loss of catalytic residue at I42 (P = 0.1167);Loss of catalytic residue at I42 (P = 0.1167);
MVP		0.94
MPC		0.28
ClinPred		0.66	D
GERP RS		6.0
Varity_R		0.77
gMVP		0.33

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs80357163; hg19: chr17-41267753;