17-43091014-C-T

Position:

chr17-43091014-C-T

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 2P and 5B. PM1BP4_StrongBP6

The NM_007294.4(BRCA1):c.4115G>A(p.Cys1372Tyr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000558 in 1,612,666 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000055 ( 0 hom. )

Consequence

BRCA1
NM_007294.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:6B:4

Conservation

PhyloP100: 0.554

Variant links:

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -3 ACMG points.

PM1

In a compositionally_biased_region Polar residues (size 33) in uniprot entity BRCA1_HUMAN there are 27 pathogenic changes around while only 6 benign (82%) in NM_007294.4

BP4

Computational evidence support a benign effect (MetaRNN=0.035226762).

BP6

Variant 17-43091014-C-T is Benign according to our data. Variant chr17-43091014-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 55105.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=3, Uncertain_significance=5}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
BRCA1	NM_007294.4 linkuse as main transcript	c.4115G>A	p.Cys1372Tyr	missense_variant	11/23	ENST00000357654.9	NP_009225.1	P38398-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
BRCA1	ENST00000357654.9 linkuse as main transcript	c.4115G>A	p.Cys1372Tyr	missense_variant	11/23	1	NM_007294.4	ENSP00000350283.3		P38398-1

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152224

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.000288

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.00000804

AC:

AN:

248774

Hom.:

AF XY:

0.00000744

AC XY:

AN XY:

134408

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.000101

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000888

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000548

AC:

AN:

1460442

Hom.:

Cov.:

AF XY:

0.00000688

AC XY:

AN XY:

726374

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.000154

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000270

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152224

Hom.:

Cov.:

AF XY:

0.0000134

AC XY:

AN XY:

74360

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.000288

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000510

Hom.:

Bravo

AF:

0.00000756

EpiCase

AF:

0.000109

EpiControl

AF:

0.00

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:6Benign:4

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Breast-ovarian cancer, familial, susceptibility to, 1

Uncertain:2Benign:1

Uncertain significance, no assertion criteria provided	clinical testing	Breast Cancer Information Core (BIC) (BRCA1)	Feb 20, 2004	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Baylor Genetics	Jan 16, 2024	- -
Likely benign, no assertion criteria provided	clinical testing	Department of Pathology and Laboratory Medicine, Sinai Health System	-	The BRCA1 p.Cys1372Tyr variant was identified in the literature in one in silico study, where the authors found it to be neutral or of little clinical significance (Abkevich 2004). The variant was also reported in dbSNP (ID: rs55848034) â€šÃ„Ãºwith unknown alleleâ€šÃ„Ã¹, LOVD, BIC (3X as a variant with unknown clinical importance), and once in UMD as an unclassified variant. Within the UMD record it was reported to co-occur with a known pathogenic mutation in BRCA2 (c.5946delT, p.Ser1982ArgfsX22), increasing the likelihood that the p.Cys1372Tyr variant does not have clinical significance. In addition, computation analyses (PolyPhen2, SIFT, Align GVGD) do not suggest a high likelihood of impact to the protein and the p.Cys1372 residue is poorly conserved through evolution, with the variant amino acid (Tyr) present in other species (including orangutan, macaque, mouse, dog, and opossum), increasing the likelihood that this may be a benign variant. Although the variant occurs outside of the splicing consensus sequence, three in-silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE) predict a greater than 10% difference in splicing; however, this information is not predictive enough to assume pathogenicity. In summary, based on the above information, the clinical significance of this variant cannot be determined with certainty at this time although we would lean towards a more benign role for this variant. This variant is classified as predicted benign. -

not provided

Uncertain:1Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Aug 19, 2024	The BRCA1 c.4115G>A (p.Cys1372Tyr) variant has been reported in the published literature as neutral or of little clinical significance (PMIDs: 15235020 (2004) and 28781887 (2016)). It was also reported in an individual with advanced cancer (PMID: 28873162 (2017)). Transcription activation assays found that this variant performed similar to the wild-type, however, the effect on the other protein functions of BRCA1 were not assessed in these studies (PMIDs: 28781887 (2016) and 30765603 (2019)). The frequency of this variant in the general population, 0.000008 (2/248774 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is uninformative in the assessment of its pathogenicity. Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded predictions that this variant is benign. Based on the available information, we are unable to determine the clinical significance of this variant. -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 10, 2021	This variant is associated with the following publications: (PMID: 15235020, 12955082, 16267036, 28873162, 28781887, 29280214, 15343273, 22737296) -

Hereditary cancer-predisposing syndrome

Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Mar 25, 2019	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. -
Likely benign, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Nov 13, 2017	- -

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Jul 05, 2022

Variant summary: BRCA1 c.4115G>A (p.Cys1372Tyr) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 8e-06 in 248774 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.4115G>A has been reported in the literature in individual(s) affected with cancer, including Hereditary Breast And Ovarian Cancer Syndrome (Judkins_2005, Mandelker_2017). These reports do not provide unequivocal conclusions about association of the variant with Hereditary Breast And Ovarian Cancer Syndrome. Co-occurrence with pathogenic variants has been reported in one sample (BRCA1 c.3607C>T, p.Arg1203X; BRCA2 c.5946delT, p.Ser1982ArgfsX22; UMD), providing supporting evidence for a benign role. In a transcriptional activation assay, the variant was found to have approximately 84% the activity of the wildtype BRCA1 protein, suggesting it has minimal impact on protein function (Woods_2016). Using a computational tool that incorporated the results of this functional assay to predict the likelihood of pathogenicity, the variant was classified as likely not pathogenic/non-pathogenic (Woods_2016, Fernandes_2019). Six assessments for this variant have been submitted to ClinVar after 2014 (likely benign n=3, VUS n=3). Based on the evidence outlined above, the variant was classified as VUS-possibly benign. -

Breast and/or ovarian cancer

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario

Jun 26, 2020

- -

Hereditary breast ovarian cancer syndrome

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Dec 24, 2023

This sequence change replaces cysteine, which is neutral and slightly polar, with tyrosine, which is neutral and polar, at codon 1372 of the BRCA1 protein (p.Cys1372Tyr). This variant is present in population databases (rs55848034, gnomAD 0.01%). This missense change has been observed in individual(s) with unspecified cancer (PMID: 28873162). ClinVar contains an entry for this variant (Variation ID: 55105). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt BRCA1 protein function with a negative predictive value of 95%. Experimental studies have shown that this missense change does not substantially affect BRCA1 function (PMID: 28781887, 30765603). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.049

BayesDel_addAF

Uncertain

0.028

BayesDel_noAF

Benign

-0.20

CADD

Benign

3.7

DANN

Benign

0.29

DEOGEN2

Benign

0.085

.;T;.;.;.;.;.;T;.;T

Eigen

Benign

-0.77

Eigen_PC

Benign

-0.77

FATHMM_MKL

Benign

0.0089

LIST_S2

Benign

0.63

T;T;T;T;T;T;T;T;T;T

M_CAP

Benign

0.015

MetaRNN

Benign

0.035

T;T;T;T;T;T;T;T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

-1.8

.;N;N;.;.;.;.;.;.;.

PrimateAI

Benign

0.31

PROVEAN

Benign

2.4

N;N;N;N;N;N;N;N;N;N

REVEL

Uncertain

0.45

Sift

Benign

0.61

T;T;T;T;T;T;T;T;T;T

Sift4G

Benign

0.99

T;T;T;T;T;T;.;.;T;.

Polyphen

0.0

.;B;.;.;.;B;.;B;.;.

Vest4

0.28

MVP

0.42

MPC

0.14

ClinPred

0.010

GERP RS

2.3

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.021

gMVP

0.079

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over