rs730881448

Positions:

• chr17-43104143-A-C
• chr17-43104143-A-G
• chr17-43104143-A-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_007294.4(BRCA1):​c.420T>G​(p.Ser140Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: BRCA1 NM_007294.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.609

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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.15798351).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
BRCA1	NM_007294.4	c.420T>G	p.Ser140Arg	missense_variant	6/23	ENST00000357654.9	NP_009225.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
BRCA1	ENST00000357654.9	c.420T>G	p.Ser140Arg	missense_variant	6/23	1	NM_007294.4	ENSP00000350283	P4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Hereditary cancer-predisposing syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 15, 2014

The p.S140R variant (also known as c.420T>G or 539T>G), located in coding exon 5 of the BRCA1 gene, results from a T to G substitution at nucleotide position 420. The serine at codon 140 is replaced by arginine, an amino acid with dissimilar properties. This variant was not reported in population based cohorts in the following databases: Database of Single Nucleotide Polymorphisms (dbSNP), NHLBI Exome Sequencing Project (ESP), and 1000 Genomes Project. In the ESP, this variant was not observed in 6503 samples (13006 alleles) with coverage at this position. To date, this alteration has been detected with an allele frequency of approximately 0.002% (greater than 64000 alleles tested) in our clinical cohort. This amino acid position is not 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 p.S140R remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.16
BayesDel_addAF	Pathogenic	0.24	D
BayesDel_noAF	Uncertain	0.11
CADD	Benign	6.5
DANN	Uncertain	1.0
DEOGEN2	Benign	0.14	.;T;.;.;.;.;.;T;.;T;.;T;T;.;T;T
Eigen	Benign	-0.58
Eigen_PC	Benign	-0.67
FATHMM_MKL	Benign	0.079	N
LIST_S2	Benign	0.82	T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T
M_CAP	Uncertain	0.21	D
MetaRNN	Benign	0.16	T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.99	T
MutationAssessor	Uncertain	2.3	M;M;M;M;.;M;.;.;.;.;.;.;.;.;.;.
MutationTaster	Benign	1.0	N;N;N;N;N;N;N;N;N;N;N;N;N;N
PrimateAI	Benign	0.28	T
PROVEAN	Benign	-1.4	N;N;N;N;N;N;N;N;N;N;N;.;N;N;N;N
REVEL	Uncertain	0.59
Sift	Benign	0.17	T;D;D;T;D;T;D;T;T;T;D;.;D;D;D;T
Sift4G	Benign	0.11	T;D;D;T;T;T;.;.;D;.;D;.;D;.;D;.
Polyphen		0.16, 1.0, 0.93	.;B;.;.;.;D;.;D;.;.;P;.;.;.;.;.
Vest4		0.24
MutPred		0.23		Gain of MoRF binding (P = 0.0221);Gain of MoRF binding (P = 0.0221);Gain of MoRF binding (P = 0.0221);Gain of MoRF binding (P = 0.0221);.;Gain of MoRF binding (P = 0.0221);.;Gain of MoRF binding (P = 0.0221);.;.;Gain of MoRF binding (P = 0.0221);Gain of MoRF binding (P = 0.0221);Gain of MoRF binding (P = 0.0221);.;Gain of MoRF binding (P = 0.0221);Gain of MoRF binding (P = 0.0221);
MVP		0.78
MPC		0.093
ClinPred		0.42	T
GERP RS		0.60
Varity_R		0.081
gMVP		0.37

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: rs730881448; hg19: chr17-41256160;