chr17-43067685-T-C

Position:

• chr17-43067685-T-C

Variant summary

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

The NM_007294.4(BRCA1):​c.4997A>G​(p.Tyr1666Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000274 in 1,459,374 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. Y1666Y) has been classified as Benign.

• Frequency:
  • Genomes: not found (cov: 30)
  • Exomes 𝑓: 0.0000027 (0 hom.)
• Consequence: BRCA1 NM_007294.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:4 B:1 O:1
• Conservation: PhyloP100: 3.27

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 domain BRCT 1 (size 94) in uniprot entity BRCA1_HUMAN there are 74 pathogenic changes around while only 17 benign (81%) in NM_007294.4
• PM2: Very rare variant in population databases, with high coverage
• BP6: Variant 17-43067685-T-C is Benign according to our data. Variant chr17-43067685-T-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 55352.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, not_provided=1, Uncertain_significance=4}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
BRCA1	NM_007294.4	c.4997A>G	p.Tyr1666Cys	missense_variant	16/23	ENST00000357654.9	NP_009225.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
BRCA1	ENST00000357654.9	c.4997A>G	p.Tyr1666Cys	missense_variant	16/23	1	NM_007294.4	ENSP00000350283	P4

Frequencies

GnomAD3 genomes Cov.: 30

GnomAD3 exomes AF: 0.0000159 AC: 4 AN: 251340 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 135852

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000116

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000274 AC: 4 AN: 1459374 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 726222

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000671

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 9.01e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 30

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:4 Benign:1 Other:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Hereditary cancer-predisposing syndrome Uncertain:1 Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	May 11, 2020	This missense variant replaces tyrosine with cysteine at codon 1666 of the BRCA1 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). This variant has been reported to be functional in a haploid cell proliferation assay (PMID: 30209399). This variant has been reported in one individual affected with breast cancer (PMID: 18835712) and in one family referred to breast and ovarian cancer genetic testing (PMID: 28324225). This variant has been identified in 4/251340 chromosomes 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. -
Likely benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Apr 07, 2022	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 Uncertain:1 Other:1

not provided, no classification provided	in vitro	Brotman Baty Institute, University of Washington	-	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Baylor Genetics	Jan 03, 2024	- -

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Feb 17, 2016

This variant is denoted BRCA1 c.4997A>G at the cDNA level, p.Tyr1666Cys (Y1666C) at the protein level, and results in the change of a Tyrosine to a Cysteine (TAC>TGC). This variant, previously published as BRCA1 5116A>G using alternate nomenclature, has been reported in at least one individual with early-onset breast cancer (Haitian 2008). BRCA1 Tyr1666Cys 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 Tyrosine and Cysteine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. BRCA1 Tyr1666Cys occurs at a position that is not conserved and is located within the DNA binding domain as well as a region known to interact with multiple other proteins (Narod 2004, 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 Tyr1666Cys is a pathogenic or benign variant. We consider it to be 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

Dec 06, 2023

This sequence change replaces tyrosine, which is neutral and polar, with cysteine, which is neutral and slightly polar, at codon 1666 of the BRCA1 protein (p.Tyr1666Cys). This variant is present in population databases (rs397509216, gnomAD 0.009%). This missense change has been observed in individual(s) with breast cancer and family history of hereditary breast or ovarian cancer (PMID: 18835712, 28324225). This variant is also known as c.5116A>G. ClinVar contains an entry for this variant (Variation ID: 55352). Advanced modeling performed at Invitae incorporating data from internal and/or published experimental studies (PMID: 30209399) indicates that this missense variant is not expected to disrupt BRCA1 function with a negative predictive value of 95%. Experimental studies have shown that this missense change does not substantially affect BRCA1 function (PMID: 30209399). 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.064
BayesDel_addAF	Uncertain	0.14	D
BayesDel_noAF	Pathogenic	0.16
CADD	Benign	22
DANN	Uncertain	1.0
DEOGEN2	Benign	0.14	.;T;.;.;T;.;.;.;T;.
Eigen	Benign	-0.011
Eigen_PC	Benign	-0.023
FATHMM_MKL	Uncertain	0.84	D
LIST_S2	Uncertain	0.96	D;D;D;D;D;D;D;D;D;D
M_CAP	Pathogenic	0.45	D
MetaRNN	Uncertain	0.43	T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.70	T
MutationAssessor	Benign	0.34	.;N;.;.;.;.;.;.;.;.
MutationTaster	Benign	1.0	D;D;D;D;N;N;N;N;N;N;N;N;N;N
PrimateAI	Benign	0.32	T
PROVEAN	Uncertain	-2.8	D;N;.;D;.;N;N;D;N;D
REVEL	Uncertain	0.55
Sift	Uncertain	0.0050	D;D;.;D;.;D;D;D;D;D
Sift4G	Uncertain	0.020	D;D;D;D;D;D;D;.;.;T
Polyphen		0.96, 0.90	.;D;.;.;.;.;.;.;P;.
Vest4		0.53
MVP		0.83
MPC		0.17
ClinPred		0.31	T
GERP RS		4.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.50
gMVP		0.42

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs397509216; hg19: chr17-41219702;