chr17-43093693-C-G

Position:

• chr17-43093693-C-G

Variant summary

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

The NM_007294.4(BRCA1):​c.1838G>C​(p.Arg613Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. R613R) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: BRCA1 NM_007294.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.859

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.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
BRCA1	NM_007294.4	c.1838G>C	p.Arg613Thr	missense_variant	10/23	ENST00000357654.9	NP_009225.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
BRCA1	ENST00000357654.9	c.1838G>C	p.Arg613Thr	missense_variant	10/23	1	NM_007294.4	ENSP00000350283	P4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 34

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.26
BayesDel_addAF	Pathogenic	0.19	D
BayesDel_noAF	Uncertain	0.040
CADD	Benign	21
DANN	Uncertain	0.98
DEOGEN2	Uncertain	0.65	D;.;.;.;T;T;.
Eigen	Uncertain	0.46
Eigen_PC	Uncertain	0.30
FATHMM_MKL	Uncertain	0.80	D
LIST_S2	Pathogenic	0.98	D;D;D;D;D;D;D
M_CAP	Pathogenic	0.59	D
MetaRNN	Uncertain	0.74	D;D;D;D;D;D;D
MetaSVM	Uncertain	-0.0098	T
MutationAssessor	Pathogenic	3.8	H;H;.;.;.;.;.
MutationTaster	Benign	1.0	D;D;D;D;D;D;D;D;N;N;N;N;N;N
PrimateAI	Benign	0.26	T
PROVEAN	Pathogenic	-5.4	D;D;D;D;.;D;D
REVEL	Pathogenic	0.68
Sift	Uncertain	0.0010	D;D;D;D;.;D;D
Sift4G	Uncertain	0.016	D;D;D;D;.;D;.
Polyphen		1.0	D;.;.;D;.;.;.
Vest4		0.46
MutPred		0.55		Gain of phosphorylation at R613 (P = 0.0357);Gain of phosphorylation at R613 (P = 0.0357);.;Gain of phosphorylation at R613 (P = 0.0357);.;Gain of phosphorylation at R613 (P = 0.0357);.;
MVP		0.88
MPC		0.50
ClinPred		0.87	D
GERP RS		1.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.6
Varity_R		0.27
gMVP		0.23

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr17-41245710;