chr17-43124078-G-T

Position:

• chr17-43124078-G-T

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 4P and 2B. PM1 PM2 BP4_Moderate

The ENST00000357654.9(BRCA1):​c.19C>A​(p.Arg7Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,166 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. 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. R7C) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: BRCA1 ENST00000357654.9 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1 O:1
• Conservation: PhyloP100: 1.36

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 2 ACMG points.

• PM1: In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 8 benign, 14 uncertain in ENST00000357654.9
• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.19609499).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
BRCA1	NM_007294.4	c.19C>A	p.Arg7Ser	missense_variant	2/23	ENST00000357654.9	NP_009225.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
BRCA1	ENST00000357654.9	c.19C>A	p.Arg7Ser	missense_variant	2/23	1	NM_007294.4	ENSP00000350283	P4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000398 AC: 1 AN: 251054 Hom.: 0 AF XY: 0.00000737 AC XY: 1 AN XY: 135680

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461166 Hom.: 0 Cov.: 30 AF XY: 0.00000275 AC XY: 2 AN XY: 726934

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000232

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ExAC AF: 0.00000824 AC: 1

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1 Other:1

Revision: criteria provided, single submitter

Submissions by phenotype

Hereditary breast ovarian cancer syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Apr 24, 2019

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, but this prediction has not been confirmed by published transcriptional studies. This variant has been reported to have conflicting or insufficient data to determine the effect on BRCA1 protein function (PMID: 30209399). This variant has not been reported in the literature in individuals with BRCA1-related conditions. This variant is present in population databases (rs80356994, ExAC 0.006%). This sequence change replaces arginine with serine at codon 7 of the BRCA1 protein (p.Arg7Ser). The arginine residue is moderately conserved and there is a moderate physicochemical difference between arginine and serine. -

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

not provided, no classification provided

in vitro

Brotman Baty Institute, University of Washington

-

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.27
BayesDel_addAF	Uncertain	0.077	D
BayesDel_noAF	Uncertain	-0.030
CADD	Benign	15
DANN	Benign	0.90
DEOGEN2	Benign	0.12	.;T;.;.;.;T;.;T;T;.;T;T;.;T
Eigen	Benign	-0.36
Eigen_PC	Benign	-0.34
FATHMM_MKL	Benign	0.15	N
LIST_S2	Uncertain	0.90	D;D;D;D;D;D;D;T;D;T;D;D;T;D
M_CAP	Uncertain	0.21	D
MetaRNN	Benign	0.20	T;T;T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.50	T
MutationAssessor	Benign	0.39	N;N;N;N;N;.;.;.;.;.;.;.;.;.
MutationTaster	Benign	1.0	N;N;N;N;N;N;N;N;N;N;N;N;N;N
PrimateAI	Benign	0.23	T
PROVEAN	Benign	-0.12	N;N;N;N;N;N;N;.;N;N;N;N;N;.
REVEL	Uncertain	0.50
Sift	Benign	0.73	T;D;D;T;T;T;D;.;D;D;D;T;T;.
Sift4G	Uncertain	0.015	D;T;T;D;D;.;D;.;D;.;D;.;.;.
Polyphen		0.21, 0.76, 0.29	.;B;.;.;P;.;B;.;.;.;.;.;.;.
Vest4		0.39
MutPred		0.41		Gain of disorder (P = 0.0652);Gain of disorder (P = 0.0652);Gain of disorder (P = 0.0652);Gain of disorder (P = 0.0652);Gain of disorder (P = 0.0652);Gain of disorder (P = 0.0652);Gain of disorder (P = 0.0652);Gain of disorder (P = 0.0652);Gain of disorder (P = 0.0652);Gain of disorder (P = 0.0652);Gain of disorder (P = 0.0652);Gain of disorder (P = 0.0652);Gain of disorder (P = 0.0652);Gain of disorder (P = 0.0652);
MVP		0.80
MPC		0.091
ClinPred		0.16	T
GERP RS		2.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.32
gMVP		0.43

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.15		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: rs80356994; hg19: chr17-41276095;