17-43104219-G-C

Position:

• chr17-43104219-G-C

Variant summary

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

The NM_007294.4(BRCA1):​c.344C>G​(p.Pro115Arg) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: not found (cov: 32)
• Consequence: BRCA1 NM_007294.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 3.80

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]

BRCA1 (HGNC:):

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.344C>G	p.Pro115Arg	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.344C>G	p.Pro115Arg	missense_variant	6/23	1	NM_007294.4	ENSP00000350283.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Pathogenic	0.31	D
BayesDel_noAF	Pathogenic	0.20
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.23	.;T;.;.;.;.;.;T;.;T;.;T;T;.;T;T;.
Eigen	Uncertain	0.49
Eigen_PC	Uncertain	0.48
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Uncertain	0.95	D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D
M_CAP	Pathogenic	0.73	D
MetaRNN	Uncertain	0.58	D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Uncertain	2.4	M;M;M;M;.;M;.;.;.;.;.;.;.;.;.;.;.
PrimateAI	Benign	0.30	T
PROVEAN	Benign	-0.84	N;N;N;N;N;N;N;D;N;N;N;.;N;N;N;D;D
REVEL	Uncertain	0.60
Sift	Uncertain	0.0070	D;D;D;T;D;T;D;D;D;D;D;.;D;D;D;T;D
Sift4G	Benign	0.25	T;D;D;D;D;D;.;.;D;.;D;.;D;.;D;.;.
Polyphen		0.99, 1.0, 0.93	.;D;.;.;.;D;.;.;.;.;P;.;.;.;.;.;.
Vest4		0.40
MutPred		0.23		Loss of methylation at K110 (P = 0.0988);Loss of methylation at K110 (P = 0.0988);Loss of methylation at K110 (P = 0.0988);Loss of methylation at K110 (P = 0.0988);.;Loss of methylation at K110 (P = 0.0988);.;Loss of methylation at K110 (P = 0.0988);.;.;Loss of methylation at K110 (P = 0.0988);Loss of methylation at K110 (P = 0.0988);Loss of methylation at K110 (P = 0.0988);.;Loss of methylation at K110 (P = 0.0988);Loss of methylation at K110 (P = 0.0988);.;
MVP		0.91
MPC		0.35
ClinPred		0.92	D
GERP RS		4.3
Varity_R		0.13
gMVP		0.43

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: chr17-41256236; COSMIC: COSV58797158; COSMIC: COSV58797158;