rs1555593567

Positions:

• chr17-43095886-T-A
• chr17-43095886-T-C

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_007294.4(BRCA1):​c.630A>T​(p.Gln210His) 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. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. Q210R) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 31)
• Consequence: BRCA1 NM_007294.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.43

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 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.36449766).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
BRCA1	NM_007294.4	c.630A>T	p.Gln210His	missense_variant	9/23	ENST00000357654.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
BRCA1	ENST00000357654.9	c.630A>T	p.Gln210His	missense_variant	9/23	1	NM_007294.4	P4

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 31

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.21
BayesDel_addAF	Pathogenic	0.31	D
BayesDel_noAF	Pathogenic	0.21
CADD	Benign	22
DANN	Uncertain	1.0
Eigen	Benign	-0.040
Eigen_PC	Benign	-0.045
FATHMM_MKL	Benign	0.67	D
LIST_S2	Uncertain	0.91	D;D;D;D;D;D;D;D;D;D;D;D;D
M_CAP	Pathogenic	0.64	D
MetaRNN	Benign	0.36	T;T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Uncertain	0.75	D
MutationAssessor	Uncertain	2.4	M;M;M;M;.;M;.;.;.;.;.;.;.
MutationTaster	Benign	0.99	D;D;D;D;D;N;N;N;N;N;N;N;N;N
PrimateAI	Benign	0.25	T
PROVEAN	Benign	-1.2	N;N;N;N;N;N;N;N;N;N;N;N;N
REVEL	Uncertain	0.61
Sift	Uncertain	0.018	D;D;D;T;D;T;D;D;D;D;D;D;D
Sift4G	Uncertain	0.023	D;D;T;T;T;T;.;T;D;D;.;D;.
Polyphen		0.99, 0.99, 0.069	.;D;.;.;.;D;.;.;B;.;.;.;.
Vest4		0.28
MutPred		0.26		Gain of catalytic residue at Q210 (P = 0.0643);Gain of catalytic residue at Q210 (P = 0.0643);Gain of catalytic residue at Q210 (P = 0.0643);Gain of catalytic residue at Q210 (P = 0.0643);.;Gain of catalytic residue at Q210 (P = 0.0643);.;.;Gain of catalytic residue at Q210 (P = 0.0643);Gain of catalytic residue at Q210 (P = 0.0643);.;Gain of catalytic residue at Q210 (P = 0.0643);.;
MVP		0.93
MPC		0.14
ClinPred		0.64	D
GERP RS		3.5
Varity_R		0.11
gMVP		0.45

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		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: chr17-41247903;