17-43106499-C-G

Position:

• chr17-43106499-C-G

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM1 PM2

The NM_007294.4(BRCA1):​c.169G>C​(p.Gly57Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000657 in 152,122 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency: Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
• Consequence: BRCA1 NM_007294.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3 B:1 O:1
• Conservation: PhyloP100: 1.38

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]

BRCA1 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 4 ACMG points.

• PM1: In a zinc_finger_region RING-type (size 41) in uniprot entity BRCA1_HUMAN there are 65 pathogenic changes around while only 6 benign (92%) in NM_007294.4
• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
BRCA1	NM_007294.4	c.169G>C	p.Gly57Arg	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.169G>C	p.Gly57Arg	missense_variant	4/23	1	NM_007294.4	ENSP00000350283.3

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152122 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome Cov.: 28

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152122 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 74312

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000192

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:3 Benign:1 Other:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

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

Uncertain significance, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Mar 10, 2016	- -
not provided, no classification provided	in vitro	Brotman Baty Institute, University of Washington	-	- -
Likely benign, criteria provided, single submitter	curation	Lupski Lab, Baylor-Hopkins CMG, Baylor College of Medicine	Apr 12, 2024	Each variant was annotated with functional scores from MAVE data which was translated into functional evidence codes. All other evidence codes and combining criteria were adhered to as closely as possible based on the ClinGen VCEP (Variant Curation Expert Panel) gene-specific recommendations. See Supplemental Figure 34 of final paper (Supp Fig. 28 in preprint: doi:10.1101/2024.04.11.24305690) for a table to see which lines of evidence we did not have data for. The ClinGen VCEPs are highly regarded as the gold-standard for gene-specific variant curation and are developed after extensive evaluation of the evidence by clinical and scientific experts for the particular gene to classify genomic variants on a spectrum from pathogenic to benign using the 2015 ACMG/AMP Variant Interpretation Guidelines as a backbone (PMID: 25741868). Reclassification of these VUS variants from gnomAD or All of Us focused only on variants originally prescribed as VUS in ClinVar. To ensure reproducibility, transparency, and increased throughput, all the procedures for annotating variants and assigning evidence codes were codified using Python. All code has been made freely available and is linked in the Code Availability section and all reclassified variants with evidence codes used can be found in Tables S18-19 (preprint: doi:10.1101/2024.04.11.24305690). For the MAVE data, the clinical curation and clinical strength assignment as per the ClinGen recommendations in Brnich et al. (2020) (PMID: 31892348) for or against pathogenicity or benignity of each of these MAVE datasets utilized in this study were previously published in Fayer et al. (2021) (PMID: 34793697).In brief, for BRCA1 variants, if a variant was categorized as FUNC (functional), it was assigned BS3 evidence and no PS3 evidence, whereas if it was categorized as LOF (loss of function), the variant was assigned PS3 evidence and no BS3 evidence. Variants categorized as INT (intermediate) were left unannotated. For the BRCA1 combining criteria, greater than or equal to 1 criteria of strong benign evidence was enough to reclassify the VUS as Likely Benign. This variant GRCh37:17:41258516:C>G was assigned evidence codes ['BS3'] and an overall classification of Likely Benign -

Hereditary cancer-predisposing syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 19, 2017

The p.G57R variant (also known as c.169G>C), located in coding exon 3 of the BRCA1 gene, results from a G to C substitution at nucleotide position 169. The glycine at codon 57 is replaced by arginine, an amino acid with dissimilar properties. This alteration was found to prevent the interaction between the BRCA1 protein and the E2 ubiquitin conjugating enzyme UbcH5a (Morris JR et al. Hum. Mol. Genet., 2006 Feb;15:599-606). This amino acid position is well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

Hereditary breast ovarian cancer syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jun 15, 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. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. Experimental studies have shown that this missense change does not substantially affect BRCA1 function (PMID: 30209399). 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. ClinVar contains an entry for this variant (Variation ID: 252391). This missense change has been observed in individual(s) with breast cancer (PMID: 19619314). This variant is present in population databases (no rsID available, gnomAD 0.06%). This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 57 of the BRCA1 protein (p.Gly57Arg). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.85
BayesDel_addAF	Pathogenic	0.25	D
BayesDel_noAF	Uncertain	0.13
CADD	Pathogenic	26
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.45	.;T;.;.;.;.;T;.;.;T;T;T;T;.
Eigen	Uncertain	0.46
Eigen_PC	Uncertain	0.49
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Uncertain	0.94	D;D;D;D;D;D;D;D;D;D;D;D;D;D
M_CAP	Pathogenic	0.46	D
MetaRNN	Uncertain	0.61	D;D;D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Uncertain	0.21	D
MutationAssessor	Benign	0.46	N;N;N;N;.;N;.;.;.;.;.;.;.;.
PrimateAI	Uncertain	0.63	T
PROVEAN	Benign	-0.45	N;N;N;N;N;N;N;N;N;.;N;N;D;.
REVEL	Uncertain	0.60
Sift	Uncertain	0.0060	D;D;D;D;D;D;D;D;D;.;D;D;D;.
Sift4G	Uncertain	0.027	D;D;D;T;D;T;.;D;D;.;D;D;.;.
Polyphen		1.0, 1.0, 1.0	.;D;.;.;.;D;.;.;D;.;.;.;.;.
Vest4		0.52
MutPred		0.51		Gain of solvent accessibility (P = 0.0014);Gain of solvent accessibility (P = 0.0014);Gain of solvent accessibility (P = 0.0014);Gain of solvent accessibility (P = 0.0014);.;Gain of solvent accessibility (P = 0.0014);Gain of solvent accessibility (P = 0.0014);.;Gain of solvent accessibility (P = 0.0014);Gain of solvent accessibility (P = 0.0014);Gain of solvent accessibility (P = 0.0014);Gain of solvent accessibility (P = 0.0014);Gain of solvent accessibility (P = 0.0014);.;
MVP		0.92
MPC		0.48
ClinPred		0.92	D
GERP RS		5.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.50
gMVP		0.43

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.20		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.20		Position offset: -43

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs879255289; hg19: chr17-41258516;