rs80356859

chr17-43093759-A-Gchr17-43093759-A-T

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 0P and 2B. BP4 BP6

The NM_007294.4(BRCA1):c.1772T>C(p.Ile591Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000041 in 1,461,684 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. I591M) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000041 (0 hom.)
• Consequence: BRCA1 NM_007294.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:5 B:6
• Conservation: PhyloP100: -0.106

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_benign. Variant got -2 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.38131168).
• BP6: Variant 17-43093759-A-G is Benign according to our data. Variant chr17-43093759-A-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 54345.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=5, Uncertain_significance=3}. Variant chr17-43093759-A-G is described in Lovd as [Likely_benign].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
BRCA1	NM_007294.4	c.1772T>C	p.Ile591Thr	missense_variant	10/23	ENST00000357654.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
BRCA1	ENST00000357654.9	c.1772T>C	p.Ile591Thr	missense_variant	10/23	1	NM_007294.4	P4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000797 AC: 2 AN: 251098 Hom.: 0 AF XY: 0.00000737 AC XY: 1 AN XY: 135750

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000176

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000410 AC: 6 AN: 1461684 Hom.: 0 Cov.: 34 AF XY: 0.00000138 AC XY: 1 AN XY: 727138

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000360

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 32

Bravo AF: 0.0000113

ExAC AF: 0.00000824 AC: 1

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:5 Benign:6

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Hereditary cancer-predisposing syndrome Benign:3

Likely benign, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Apr 08, 2022	- -
Likely benign, criteria provided, single submitter	curation	University of Washington Department of Laboratory Medicine, University of Washington	Mar 23, 2023	Missense variant in a coldspot region where missense variants are very unlikely to be pathogenic (PMID:31911673). -
Likely benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Nov 06, 2018	This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

not provided Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	May 01, 2022	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Sep 15, 2022	The frequency of this variant in the general population, 0.000008 (2/251098 chromosomes, http://gnomad.broadinstitute.org), is uninformative in assessment of its pathogenicity. In the published literature, the variant has been reported in individuals with breast cancer (PMID: 25777348 (2015), 22476429 (2012)) and individuals with glioblastomas (PMID: 26933808 (20016)). Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded conflicting predictions that this variant is benign or damaging. Based on the available information, we are unable to determine the clinical significance of this variant. -

not specified Uncertain:1 Benign:1

Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Oct 30, 2017	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -
Uncertain significance, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Oct 01, 2018	Variant summary: BRCA1 c.1772T>C (p.Ile591Thr) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 1.2e-05 in 245912 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.1772T>C has been reported in the literature in individuals affected with Hereditary Breast and Ovarian Cancer. These reports do not provide unequivocal conclusions about association of the variant with Hereditary Breast and Ovarian Cancer. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation and all classified the variant as likely benign. Based on the evidence outlined above, the variant was classified as uncertain significance until additional information becomes available. -

Breast-ovarian cancer, familial, susceptibility to, 1 Uncertain:1 Benign:1

Uncertain significance, no assertion criteria provided	clinical testing	Breast Cancer Information Core (BIC) (BRCA1)	Dec 23, 2003	- -
Benign, no assertion criteria provided	clinical testing	Sharing Clinical Reports Project (SCRP)	Oct 27, 2011	- -

Hereditary breast ovarian cancer syndrome Uncertain:1 Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Institute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C.	Apr 02, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	Invitae	Aug 28, 2023	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.31
BayesDel_addAF	Uncertain	0.12	D
BayesDel_noAF	Uncertain	0.0
Cadd	Benign	19
Dann	Uncertain	0.99
DEOGEN2	Uncertain	0.49	T;.;.;.;T;T;.
Eigen	Benign	-0.015
Eigen_PC	Benign	-0.13
FATHMM_MKL	Benign	0.22	N
LIST_S2	Uncertain	0.88	D;D;D;D;D;D;D
M_CAP	Pathogenic	0.48	D
MetaRNN	Benign	0.38	T;T;T;T;T;T;T
MetaSVM	Uncertain	-0.056	T
MutationAssessor	Uncertain	2.4	M;M;.;.;.;.;.
MutationTaster	Benign	1.0	D;D;D;D;D;D;D;D;N;N;N;N;N;N
PrimateAI	Benign	0.38	T
PROVEAN	Uncertain	-4.3	D;D;D;D;.;D;D
REVEL	Pathogenic	0.66
Sift	Uncertain	0.0030	D;D;D;D;.;D;D
Sift4G	Benign	0.19	T;T;T;T;.;T;.
Polyphen		0.99	D;.;.;P;.;.;.
Vest4		0.44
MutPred		0.41		Loss of stability (P = 0.0171);Loss of stability (P = 0.0171);.;Loss of stability (P = 0.0171);.;Loss of stability (P = 0.0171);.;
MVP		0.96
MPC		0.45
ClinPred		0.71	D
GERP RS		2.3
Varity_R		0.28
gMVP		0.054

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: rs80356859; hg19: chr17-41245776;