17-43106465-A-T

Position:

• chr17-43106465-A-T

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_007294.4(BRCA1):​c.203T>A​(p.Ile68Lys) 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 Uncertain significance (★★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: BRCA1 NM_007294.4 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:4 O:1
• Conservation: PhyloP100: 4.88

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 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.859

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
BRCA1	NM_007294.4	c.203T>A	p.Ile68Lys	missense_variant	4/23	ENST00000357654.9	NP_009225.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
BRCA1	ENST00000357654.9	c.203T>A	p.Ile68Lys	missense_variant	4/23	1	NM_007294.4	ENSP00000350283	P4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 28

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:4 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

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

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

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Sep 04, 2021

Variant summary: BRCA1 c.203T>A (p.Ile68Lys) 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 250482 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.203T>A has been reported in the literature as a VUS in individuals affected with breast cancer (example, Judkins_2005, Russo_2007, Gao_2020). These report(s) do not provide unequivocal conclusions about association of the variant with Hereditary Breast And Ovarian Cancer Syndrome. Multiple publications report conflicting experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in a loss of Homology Directed Repair (HDR) activity (Findlay_2018) whereas earlier studies reported proficient HDR activity, proficient BARD binding, defective E3 ligase activity and UbcH5a binding (Morris_2006, Starita_2015). Furthermore, studies reporting BRCA1 tumor suppression being dependent on the ablation of phosphoprotein binding but not on its E3 ligase activity pose a challenge in using this as a measure of molecular pathogenesis in-vivo (Shakya_BRCA1_2011). 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 uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance. -

Hereditary cancer-predisposing syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Color Diagnostics, LLC DBA Color Health

Oct 01, 2019

This missense variant replaces isoleucine with lysine at codon 68 of the BRCA1 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). Splice site prediction tools suggest that this variant may not impact RNA splicing. Functional studies had contradictory findings for this variant, reporting normal homology-directed DNA repair (PMID: 25823446) but loss-of-function in a haploid cell proliferation assay and ubiquitin E2 ligase binding and ligase activity in vitro (PMID: 30209399, 16403807). This variant has been analyzed by multifactorial analysis and classified as a variant of uncertain significance (PMID: 31131967). This variant has been reported in an individual affected with breast and/or ovarian cancer (PMID: 17221156). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. -

Hereditary breast ovarian cancer syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 10, 2023

In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. 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. ClinVar contains an entry for this variant (Variation ID: 54444). This missense change has been observed in individual(s) with breast and/or ovarian cancer (PMID: 17221156). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces isoleucine, which is neutral and non-polar, with lysine, which is basic and polar, at codon 68 of the BRCA1 protein (p.Ile68Lys). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.96
BayesDel_addAF	Pathogenic	0.42	D
BayesDel_noAF	Pathogenic	0.36
CADD	Uncertain	24
DANN	Benign	0.96
DEOGEN2	Benign	0.24	.;T;.;.;.;.;T;.;.;T;T;T;T;.
Eigen	Uncertain	0.54
Eigen_PC	Uncertain	0.52
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.95	D;D;D;D;D;D;D;D;D;D;D;D;D;D
M_CAP	Pathogenic	0.82	D
MetaRNN	Pathogenic	0.86	D;D;D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Pathogenic	0.86	D
MutationAssessor	Uncertain	2.5	M;M;M;M;.;M;.;.;.;.;.;.;.;.
MutationTaster	Benign	0.98	D;D;D;D;D;D;D;D;D;D;D;D;D;D
PrimateAI	Uncertain	0.71	T
PROVEAN	Benign	-1.3	N;N;N;N;N;N;D;N;N;.;N;N;D;.
REVEL	Pathogenic	0.84
Sift	Uncertain	0.0010	D;D;D;D;D;D;D;D;D;.;D;D;D;.
Sift4G	Uncertain	0.0020	D;D;D;D;D;D;.;D;D;.;D;D;.;.
Polyphen		0.30, 0.98, 0.97	.;B;.;.;.;D;.;.;D;.;.;.;.;.
Vest4		0.79
MutPred		0.58		Gain of disorder (P = 0.0049);Gain of disorder (P = 0.0049);Gain of disorder (P = 0.0049);Gain of disorder (P = 0.0049);.;Gain of disorder (P = 0.0049);Gain of disorder (P = 0.0049);.;Gain of disorder (P = 0.0049);Gain of disorder (P = 0.0049);Gain of disorder (P = 0.0049);Gain of disorder (P = 0.0049);Gain of disorder (P = 0.0049);.;
MVP		0.98
MPC		0.51
ClinPred		0.96	D
GERP RS		4.6
Varity_R		0.97
gMVP		0.81

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		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: rs80357116; hg19: chr17-41258482;