17-43049177-C-T

Position:

• chr17-43049177-C-T

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM1 PM2 PM5

The NM_007294.4(BRCA1):​c.5350G>A​(p.Val1784Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V1784A) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 31)
• Consequence: BRCA1 NM_007294.4 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2 O:1
• Conservation: PhyloP100: 0.338

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 Likely_pathogenic. Variant got 6 ACMG points.

• PM1: In a hotspot region, there are 8 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 6 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 chr17-43049176-A-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 868026.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
BRCA1	NM_007294.4	c.5350G>A	p.Val1784Ile	missense_variant	21/23	ENST00000357654.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
BRCA1	ENST00000357654.9	c.5350G>A	p.Val1784Ile	missense_variant	21/23	1	NM_007294.4	P4

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 31

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2 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, criteria provided, single submitter	clinical testing	Counsyl	Dec 29, 2017	- -
not provided, no classification provided	in vitro	Brotman Baty Institute, University of Washington	-	- -

Hereditary breast ovarian cancer syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Jun 21, 2018

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 missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. This variant has not been reported in the literature in individuals with BRCA1-related disease. ClinVar contains an entry for this variant (Variation ID: 409303). This variant is not present in population databases (ExAC no frequency). This sequence change replaces valine with isoleucine at codon 1784 of the BRCA1 protein (p.Val1784Ile). The valine residue is highly conserved and there is a small physicochemical difference between valine and isoleucine. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Uncertain	0.11	D
BayesDel_noAF	Uncertain	-0.080
CADD	Benign	17
DANN	Uncertain	1.0
Eigen	Benign	0.13
Eigen_PC	Benign	0.091
FATHMM_MKL	Uncertain	0.77	D
LIST_S2	Uncertain	0.96	D;D;D;D;D;D;D;D
M_CAP	Pathogenic	0.34	D
MetaRNN	Uncertain	0.61	D;D;D;D;D;D;D;D
MetaSVM	Uncertain	-0.20	T
MutationTaster	Benign	0.75	D;D;D;D;D;D;D;D;D;N;N;N;N;N
PrimateAI	Benign	0.27	T
PROVEAN	Benign	-0.37	N;N;.;.;.;.;N;N
REVEL	Uncertain	0.33
Sift	Benign	0.056	T;D;.;.;.;.;D;T
Sift4G	Uncertain	0.019	D;D;D;D;D;D;D;D
Polyphen		0.80, 0.86	.;P;.;.;.;P;.;.
Vest4		0.49
MVP		0.83
MPC		0.35
ClinPred		0.91	D
GERP RS		3.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.093
gMVP		0.32

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: rs1060502328; hg19: chr17-41201194;