17-43063910-C-T

Position:

• chr17-43063910-C-T

Variant summary

Our verdict is Pathogenic. Variant got 24 ACMG points: 24P and 0B. PS1_Very_Strong PM1 PM2 PM5 PP3_Moderate PP5_Very_Strong

The NM_007294.4(BRCA1):​c.5116G>A​(p.Gly1706Arg) 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 (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely pathogenicin ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G1706A) has been classified as Benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: BRCA1 NM_007294.4 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:4 O:1
• Conservation: PhyloP100: 4.86

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 24 ACMG points.

• PS1: Transcript NM_007294.4 (BRCA1) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in ClinVar as 267219
• PM1: In a hotspot region, there are 11 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 3 benign, 17 uncertain in NM_007294.4
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr17-43063909-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 37638.Status of the report is reviewed_by_expert_panel, 3 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.893
• PP5: Variant 17-43063910-C-T is Pathogenic according to our data. Variant chr17-43063910-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 267221.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-43063910-C-T is described in Lovd as [Pathogenic]. Variant chr17-43063910-C-T is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
BRCA1	NM_007294.4	c.5116G>A	p.Gly1706Arg	missense_variant	17/23	ENST00000357654.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
BRCA1	ENST00000357654.9	c.5116G>A	p.Gly1706Arg	missense_variant	17/23	1	NM_007294.4	P4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:4 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

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

not provided, no classification provided	in vitro	Brotman Baty Institute, University of Washington	-	- -
Pathogenic, criteria provided, single submitter	phenotyping only	UOSD Diagnostica Molecolare E Genomica, Irccs Policlinico Agostino Gemelli	Feb 05, 2015	We underline that this variant, classified as likely pathogenic, must be classified as pathogenic variant. We found this variant in two unrelated patients with familial ovarian and breast cancers. -

not provided Pathogenic:1

Likely pathogenic, no assertion criteria provided

clinical testing

Department of Pathology and Laboratory Medicine, Sinai Health System

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The p.Gly1706Arg variant was not identified in the dbSNP, NHLBI Exome Sequencing Project (Exome Variant Server), Exome Aggregation Consortium (ExAC), HGMD, LOVD, COSMIC, ClinVar, GeneInsight VariantWire, or BIC; nor was it identified by our laboratory. The variant was identified in UMD (10X as a causal variant) and in the Breast Cancer IARC. The p.Gly1706 residue is conserved across mammals and lower organisms, and four out of five computational analyses (PolyPhen-2, SIFT, AlignGVGD, MutationTaster) suggest that the p.Gly1706Arg (Arginine) variant may impact the protein. However, this information is not predictive enough to assume pathogenicity. The p.Gly1706Arg variant occurs outside of the splicing consensus sequence but 4 of 5 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) predict a greater than 10% difference in splicing; however, this is not very predictive of pathogenicity. The p.Gly1706Arg variant is located in BRCT domains and the glycine 1706 residue maps to helix ÔÅ°2. Functional and structural studies (Karchin 2007, Carvalho 2007) that applied prediction algorithms demonstrated that the hydrophobic core is disrupted in the 1706 Arginine. Functional and structural studies classified the Gly1706Arg variant as deleterious (Carvalho 2007) and as causal (Karchin 2007) by all prediction algorithms (SIFT, UMD-Predictor, Align-GVGD, PolyPhen). In summary, based on the above information, the clinical significance of this variant cannot be determined with certainty at this time although we would lean towards a more pathogenic role for this variant. This variant is classified as predicted pathogenic. -

Hereditary cancer-predisposing syndrome Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Apr 03, 2020

The p.G1706R variant (also known as c.5116G>A), located in coding exon 16 of the BRCA1 gene, results from a G to A substitution at nucleotide position 5116. The glycine at codon 1706 is replaced by arginine, an amino acid with dissimilar properties. This variant has been reported in many individuals diagnosed with breast and/or ovarian cancer (Kraus C et al. Int. J. Cancer. 2017 Jan;140:95-102; Wu X et al. Int. J. Gynecol. Cancer. 2017 10;27:1650-1657; Bhaskaran SP et al. Int. J. Cancer. 2019 08;145:962-973; Gao X et al. Hum. Mutat. 2020 Mar;41:696-708). One 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). Another study utilizing a dual luciferase TA activity assay showed that this variant had a complete lack of transactivation activity (Langerud J et al. Hum. Genomics. 2018 11;12:51). 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 majority of available evidence to date, this variant is likely to be pathogenic. -

Hereditary breast ovarian cancer syndrome Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

May 26, 2020

For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Gly1706 amino acid residue in BRCA1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 15689452, 23867111, 27272900, 15923272, 17308087, 11979449, 17924331). This suggests that this residue is clinically-significant, and that variants that disrupt this residue are likely to be disease-causing. This variant has been reported to affect BRCA1 protein function (PMID: 30209399, 30458859). This variant has been observed in individuals with a personal or family history of breast and/or ovarian cancer (PMID: 25948282, 22144684, 17262179, 27616075). This variant is also known as G602R in the literature. ClinVar contains an entry for this variant (Variation ID: 267221). This variant is not present in population databases (ExAC no frequency). This sequence change replaces glycine with arginine at codon 1706 of the BRCA1 protein (p.Gly1706Arg). The glycine residue is highly conserved and there is a moderate physicochemical difference between glycine and arginine. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.44	D
BayesDel_noAF	Pathogenic	0.39
CADD	Uncertain	26
DANN	Pathogenic	1.0
Eigen	Pathogenic	0.86
Eigen_PC	Pathogenic	0.82
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Pathogenic	0.99	D;D;D;D;D;D;D;D;D;D;D
M_CAP	Pathogenic	0.77	D
MetaRNN	Pathogenic	0.89	D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Pathogenic	0.80	D
MutationTaster	Benign	1.0	D;D;D;D;D;D;D;D;D;D;D;D;D;D
PrimateAI	Pathogenic	0.85	D
PROVEAN	Pathogenic	-6.1	D;N;.;D;.;.;N;D;D;D;D
REVEL	Pathogenic	0.88
Sift	Uncertain	0.0010	D;D;.;D;.;.;D;D;D;D;D
Sift4G	Pathogenic	0.0	D;D;D;D;D;D;D;D;.;.;D
Polyphen		0.88, 1.0	.;P;.;.;.;D;.;.;.;D;.
Vest4		0.96
MVP		0.98
MPC		0.49
ClinPred		0.99	D
GERP RS		5.8
Varity_R		0.98
gMVP		0.98

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.060		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: rs886040864; hg19: chr17-41215927;