17-43057122-A-C

Position:

• chr17-43057122-A-C

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM1 PM2 PP3_Moderate PP5_Very_Strong

The NM_007294.4(BRCA1):​c.5207T>G​(p.Val1736Gly) 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 (★★).

• Frequency: Genomes: not found (cov: 31)
• Consequence: BRCA1 NM_007294.4 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:4 U:1 B:1 O:1
• Conservation: PhyloP100: 5.55

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 14 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
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.888
• PP5: Variant 17-43057122-A-C is Pathogenic according to our data. Variant chr17-43057122-A-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 55456.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.5207T>G	p.Val1736Gly	missense_variant	19/23	ENST00000357654.9	NP_009225.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
BRCA1	ENST00000357654.9	c.5207T>G	p.Val1736Gly	missense_variant	19/23	1	NM_007294.4	ENSP00000350283	P4

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 31

ClinVar

Significance: Pathogenic/Likely pathogenic

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

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Hereditary cancer-predisposing syndrome Pathogenic:3

Likely pathogenic, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Jul 20, 2021	This missense variant replaces valine with glycine at codon 1736 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). Functional studies have shown that this variant impacts BRCA1 function in transcription activation and in a haploid cell proliferation assay (PMID: 20516115, 30209399). A different missense variant p.Val1738Ala is reported as disease-causing in ClinVar (variation ID 37648), suggesting that valine or similar amino acid at this position may be important for function. To our knowledge, this variant has not been reported in individuals affected with hereditary cancer in the literature. This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Likely Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Ambry Genetics	Nov 27, 2019	The p.V1736G pathogenic mutation (also known as c.5207T>G), located in coding exon 18 of the BRCA1 gene, results from a T to G substitution at nucleotide position 5207. The valine at codon 1736 is replaced by glycine, an amino acid with dissimilar properties. A transcription activation assay found that this variant had <80% activity relative to wildtype and was, thus, considered deleterious (Fernandes VC et al. J. Biol. Chem., 2019 04;294:5980-5992). Additionally, a functional study found that this nucleotide substitution is deleterious in a high throughput genome editing haploid cell survival assay (Findlay GM et al. Nature, 2018 10;562:217-222) and another functional study found this alteration to be severely defective in all assays (Lee MS et al. Cancer Res., 2010 Jun;70:4880-90). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. -
Likely pathogenic, criteria provided, single submitter	curation	Sema4, Sema4	Mar 16, 2022	- -

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)	Feb 20, 2004	- -
not provided, no classification provided	in vitro	Brotman Baty Institute, University of Washington	-	- -

Hereditary breast ovarian cancer syndrome Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

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

Apr 11, 2019

Variant summary: BRCA1 c.5207T>G (p.Val1736Gly) results in a non-conservative amino acid change located in the BRCT domain of 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 277208 control chromosomes. c.5207T>G has been reported in individuals affected with Hereditary Breast and Ovarian Cancer (Judkins_2005, internal data). These reports do not provide unequivocal conclusions about association of the variant with Hereditary Breast and Ovarian Cancer. A functional study demonstrated the variant to decrease protein stability, phosphopeptide binding activity, phosphopeptide binding specificity and transcriptional activity of BRCA1 (Lee_2010). Multiple studies involving computational analysis predict this variant to be pathogenic/deleterious (Cao_2019, Thompson_2016, Woods_2016, Karchin_2007, Pavlicek_2004). Different variants at the same codon such as c.5207delT, c.5207T>C are listed in databases (ClinVar, HGMD) with disease causing outcome indicating the variant to be located in a mutational hotspot and the clinical relevance of the Val1736 residue. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as likely pathogenic. -

not specified Benign:1

Benign, no assertion criteria provided

research

King Laboratory, University of Washington

Sep 01, 2019

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.88
BayesDel_addAF	Pathogenic	0.46	D
BayesDel_noAF	Pathogenic	0.42
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Benign	0.40	.;T;.;.;T;T;.;.
Eigen	Pathogenic	0.76
Eigen_PC	Pathogenic	0.71
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.92	D;D;D;D;D;D;D;D
M_CAP	Pathogenic	0.85	D
MetaRNN	Pathogenic	0.89	D;D;D;D;D;D;D;D
MetaSVM	Pathogenic	0.91	D
MutationAssessor	Pathogenic	3.3	.;M;.;.;.;.;.;.
MutationTaster	Benign	1.0	D;D;D;D;D;D;D;D;D;D;D;D;D;D
PrimateAI	Uncertain	0.49	T
PROVEAN	Pathogenic	-5.7	D;N;.;D;.;.;N;D
REVEL	Pathogenic	0.86
Sift	Pathogenic	0.0	D;D;.;D;.;.;D;D
Sift4G	Pathogenic	0.0	D;D;D;D;D;D;D;D
Polyphen		0.98, 1.0	.;D;.;.;.;D;.;.
Vest4		0.90
MVP		0.88
MPC		0.36
ClinPred		1.0	D
GERP RS		5.1
Varity_R		0.83
gMVP		0.93

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: rs45553935; hg19: chr17-41209139;