chr17-43057088-T-G

Position:

• chr17-43057088-T-G

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM1 PM2 PM5

The NM_007294.4(BRCA1):​c.5241A>C​(p.Gln1747His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as not provided (no stars). Another nucleotide change resulting in same amino acid change has been previously reported as Uncertain significancein ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. Q1747K) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 31)
• Consequence: BRCA1 NM_007294.4 missense
• Clinical Significance: not provided no classification provided O:2
• Conservation: PhyloP100: -0.0520

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 Likely_pathogenic. Variant got 6 ACMG points.

• PM1: In a hotspot region, there are 9 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 6 benign, 17 uncertain in NM_007294.4
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr17-43057089-T-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 867266.We mark this variant Likely_pathogenic, oryginal submissions are: {not_provided=1, Likely_pathogenic=1, Uncertain_significance=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
BRCA1	NM_007294.4	c.5241A>C	p.Gln1747His	missense_variant	19/23	ENST00000357654.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
BRCA1	ENST00000357654.9	c.5241A>C	p.Gln1747His	missense_variant	19/23	1	NM_007294.4	P4

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 31

ClinVar

Significance: not provided

Submissions summary: Other:2

Revision: no classification provided

Submissions by phenotype

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

not provided, no classification provided

in vitro

Brotman Baty Institute, University of Washington

-

- -

Familial cancer of breast Other:1

not provided, no classification provided

literature only

ClinVar Staff, National Center for Biotechnology Information (NCBI)

-

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.19
BayesDel_addAF	Pathogenic	0.33	D
BayesDel_noAF	Pathogenic	0.24
CADD	Benign	16
DANN	Uncertain	0.98
DEOGEN2	Benign	0.15	.;T;.;.;T;T;.;.
Eigen	Benign	-0.22
Eigen_PC	Benign	-0.18
FATHMM_MKL	Benign	0.73	D
LIST_S2	Benign	0.86	D;D;D;D;D;D;D;D
M_CAP	Pathogenic	0.32	D
MetaRNN	Uncertain	0.51	D;D;D;D;D;D;D;D
MetaSVM	Uncertain	0.059	D
MutationAssessor	Benign	1.4	.;L;.;.;.;.;.;.
MutationTaster	Benign	0.79	D;D;D;D;D;D;D;D;D;D;D;D;N;N
PrimateAI	Benign	0.29	T
PROVEAN	Uncertain	-2.9	D;N;.;D;.;.;N;D
REVEL	Uncertain	0.64
Sift	Benign	0.032	D;D;.;D;.;.;D;D
Sift4G	Uncertain	0.0040	D;D;D;D;D;D;D;D
Polyphen		0.95, 0.012	.;P;.;.;.;B;.;.
Vest4		0.54
MVP		0.73
MPC		0.085
ClinPred		0.82	D
GERP RS		1.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.49
gMVP		0.69

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: rs397509242; hg19: chr17-41209105;