rs80357061

chr17-43067616-A-Cchr17-43067616-A-Gchr17-43067616-A-T

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM1 PM2 PM5 PP3_Moderate PP5_Very_Strong

The NM_007294.4(BRCA1):c.5066T>G(p.Met1689Arg) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. M1689I) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 30)
• Consequence: BRCA1 NM_007294.4 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:10 U:1 O:1
• Conservation: PhyloP100: 5.60

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 Pathogenic. Variant got 16 ACMG points.

• PM1: In a hotspot region, there are 10 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 7 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 chr17-43067616-A-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 864899.Status of the report is criteria_provided_single_submitter, 1 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.861
• PP5: Variant 17-43067616-A-C is Pathogenic according to our data. Variant chr17-43067616-A-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 37625.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-43067616-A-C is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
BRCA1	NM_007294.4	c.5066T>G	p.Met1689Arg	missense_variant	16/23	ENST00000357654.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
BRCA1	ENST00000357654.9	c.5066T>G	p.Met1689Arg	missense_variant	16/23	1	NM_007294.4	P4

Frequencies

GnomAD3 genomes Cov.: 30

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 30

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:10 Uncertain:1 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Hereditary breast ovarian cancer syndrome Pathogenic:4

Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Aug 28, 2023	For these reasons, this variant has been classified as Pathogenic. This sequence change replaces methionine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 1689 of the BRCA1 protein (p.Met1689Arg). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with breast cancer (PMID: 15172985, 18703817, 25980754). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 37625). Advanced modeling performed at Invitae incorporating data from internal and/or published experimental studies (PMID: 30209399) indicates that this missense variant is expected to disrupt BRCA1 function. Experimental studies have shown that this missense change affects BRCA1 function (PMID: 15172985, 20516115, 27272900). Studies have shown that this missense change is associated with altered splicing resulting in unknown protein product impact (Invitae). -
Pathogenic, no assertion criteria provided	research	Research Molecular Genetics Laboratory, Women's College Hospital, University of Toronto	Jan 31, 2014	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Mar 21, 2016	The p.Met1689Arg variant in BRCA1 has been reported in at least 2 individuals wi th BRCA1-associated cancers (Mirkovic 2004, Easton 2007), segregated with diseas e in 3 affected relatives from 1 family (Mirkovic 2004), and was absent from lar ge population studies. In vitro functional studies provide some evidence that th is variant may impact protein function (Lee 2010). However, these types of assay s may not accurately represent biological function. Additionally, computational prediction tools and conservation analysis suggest that the p.Met1689Arg variant may impact the protein, though this information is not predictive enough to det ermine pathogenicity. In summary, although additional studies are required to fu lly establish its clinical significance, this variant is likely pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Aug 17, 2018	Variant summary: BRCA1 c.5066T>G (p.Met1689Arg) results in a non-conservative amino acid change located in the BRCT domain (IPR001357) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 2.9e-05 in 277098 control chromosomes (gnomAD). The variant, c.5066T>G, has been reported in the literature in multiple individuals and in at-least one large multigenerational family affected with Hereditary Breast and Ovarian Cancer where it was found to co-segregate with disease (Palma_2008, Mirkovic_2004, Easton_2007). These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in 10%-<30% of normal activity in multiple independent experimental systems measuring transactivation activity of BRCA1, protease sensitivity to assess protein folding stability, phosphopeptide binding activity, and phosphopeptide binding specificity (Carvalho_2007, Lee_2010, Mirkovic_2004). Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -

Breast-ovarian cancer, familial, susceptibility to, 1 Pathogenic:2 Uncertain:1 Other:1

Uncertain significance, no assertion criteria provided	clinical testing	Breast Cancer Information Core (BIC) (BRCA1)	May 29, 2002	- -
Pathogenic, no assertion criteria provided	clinical testing	Sharing Clinical Reports Project (SCRP)	Aug 31, 2012	- -
Pathogenic, criteria provided, single submitter	clinical testing	Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge	Oct 02, 2015	- -
not provided, no classification provided	in vitro	Brotman Baty Institute, University of Washington	-	- -

not provided Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Dec 01, 2020	Multifactorial studies suggest this variant is associated with breast and ovarian cancer (Easton 2007, Iversen 2011, Lindor 2012, Valle 2012); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed in large population cohorts (Lek 2016); Also known as 5185T>G; This variant is associated with the following publications: (PMID: 15235020, 25980754, 28781887, 27272900, 29446198, 15172985, 33087888, 21990134, 20516115, 17305420, 21447777, 32719484, 30209399, 30765603, 17924331, 21990165, 21473589, 22086652, 19706752, 18992264, 24772314, 26777316, 28277317) -
Pathogenic, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Nov 03, 2022	This variant has not been reported in large, multi-ethnic general populations (http://gnomad.broadinstitute.org). In the published literature, the variant has been reported in affected individuals and families with breast and/or ovarian cancer (PMIDs: 15172985 (2004), 16267036 (2005), and 18703817 (2008)). Experimental studies have shown that this variant is damaging to transactivation activity, protein folding stability, and phosphopeptide binding activity in both yeast and mammalian structural and functional assays (PMIDs: 14534301 (2003), 17305420 (2007), 18992264 (2009), 20516115 (2010), 21447777 (2011), 27272900 (2016), 28781887 (2016), 30209399 (2018), and 30765603 (2019)). 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 deleterious or benign. Based on the available information, this variant is classified as pathogenic. -

BRCA1-related disorder Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Apr 03, 2023

The BRCA1 c.5066T>G variant is predicted to result in the amino acid substitution p.Met1689Arg. This variant has been reported many times in individuals with breast cancer (see for examples Abkevich et al. 2004. PubMed ID: 15235020; Easton et al. 2007. PubMed ID: 17924331; Supp. Table 1 in Yurgelun et al. 2015. PubMed ID: 25980754). Functional analyses support the pathogenicity of this amino acid substitution (Lee et al. 2010. PubMed ID: 20516115; Table S4 in Woods et al. 2016. PubMed ID: 28781887). This variant has not been reported in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. This variant has been interpreted as Pathogenic/Likely Pathogenic in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/37625/). This variant is interpreted as pathogenic. -

Hereditary cancer-predisposing syndrome Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Jul 13, 2020

The p.M1689R pathogenic mutation (also known as c.5066T>G), located in coding exon 15 of the BRCA1 gene, results from a T to G substitution at nucleotide position 5066. The methionine at codon 1689 is replaced by arginine, an amino acid with similar properties. In one published study, this mutation was shown to segregate with disease in a large 3-generation family and was demonstrated to lead to a loss-of-function phenotype in both yeast and mammalian transcription assays (Mirkovic N, et al. Cancer Res. 2004 Jun; 64(11):3790-7). This alteration has been classified as likely pathogenic (p>0.9889) by multifactorial analysis (Easton D et al. Am J Hum Genet. 2007;81:873-883; Lindor NM, et al. Hum. Mutat. 2012 Jan; 33(1):8-21). One functional study found that this nucleotide substitution is deleterious in a high throughput genome editing haploid cell survival assay (Findlay GM et al. Nature, 2018 10;562:217-222). In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.93
BayesDel_addAF	Pathogenic	0.40	D
BayesDel_noAF	Pathogenic	0.34
Cadd	Uncertain	24
Dann	Uncertain	0.99
Eigen	Uncertain	0.67
Eigen_PC	Uncertain	0.64
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.93	D;D;D;D;D;D;D;D;D;D
M_CAP	Pathogenic	0.76	D
MetaRNN	Pathogenic	0.86	D;D;D;D;D;D;D;D;D;D
MetaSVM	Uncertain	0.26	D
MutationTaster	Benign	1.0	D;D;D;D;D;D;D;D;D;D;D;D;D;D
PrimateAI	Uncertain	0.74	T
PROVEAN	Uncertain	-4.3	D;N;.;D;.;N;D;D;N;D
REVEL	Pathogenic	0.75
Sift	Uncertain	0.0020	D;D;.;D;.;D;D;D;D;D
Sift4G	Uncertain	0.0030	D;D;D;D;D;D;D;.;.;D
Polyphen		0.99, 1.0	.;D;.;.;.;.;.;.;D;.
Vest4		0.96
MVP		0.98
MPC		0.45
ClinPred		0.97	D
GERP RS		5.2
Varity_R		0.97
gMVP		0.93

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.27		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.27		Position offset: -8

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs80357061; hg19: chr17-41219633;