NM_007294.4:c.5066T>G

Variant names:

• chr17-43067616-A-C
• rs80357061
• NM_007294.4:c.5066T>G

Variant summary

Our verdict is Pathogenic. The variant received 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:11 U:1
• Conservation: PhyloP100: 5.60
• Publications: 25 publications found

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 Gene-Disease associations (from GenCC):

• breast-ovarian cancer, familial, susceptibility to, 1

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Ambry Genetics, ClinGen, Labcorp Genetics (formerly Invitae), Genomics England PanelApp
• Fanconi anemia, complementation group S

  Inheritance: AR Classification: DEFINITIVE, STRONG, MODERATE, LIMITED Submitted by: G2P, Labcorp Genetics (formerly Invitae), ClinGen, Ambry Genetics
• pancreatic cancer, susceptibility to, 4

  Inheritance: AD Classification: MODERATE Submitted by: Genomics England PanelApp
• hereditary breast ovarian cancer syndrome

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• Fanconi anemia

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Pathogenic. The variant received 16 ACMG points.

• PM1: In a hotspot region, there are 27 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 10 benign, 73 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 VariationId 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 Pathogenic/Likely_pathogenic. ClinVar VariationId is 37625.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
BRCA1	NM_007294.4	c.5066T>G	p.Met1689Arg	missense_variant	Exon 16 of 23	ENST00000357654.9	NP_009225.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
BRCA1	ENST00000357654.9	c.5066T>G	p.Met1689Arg	missense_variant	Exon 16 of 23	1	NM_007294.4	ENSP00000350283.3

Frequencies

GnomAD3 genomes Cov.: 30

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 30

Alfa AF: 0.0000150 Hom.: 0

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:11 Uncertain:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Hereditary breast ovarian cancer syndrome Pathogenic:4

Sep 12, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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). Invitae Evidence Modeling incorporating data from in vitro experimental studies (PMID: 30209399) indicates that this missense variant is expected to disrupt BRCA1 function with a positive predictive value of 95%. Experimental studies have shown that this missense change affects BRCA1 function (PMID: 15172985, 20516115, 27272900). For these reasons, this variant has been classified as Pathogenic. -

Aug 17, 2018

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

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Jan 31, 2014

Research Molecular Genetics Laboratory, Women's College Hospital, University of Toronto

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: research

- -

Mar 21, 2016

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

not provided Pathogenic:3

Apr 14, 2025

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Multifactorial studies suggest this variant is associated with breast and ovarian cancer (PMID: 21447777, 21990165, 21990134, 17924331); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis is inconclusive as to whether the variant alters gene splicing. In the absence of RNA/functional studies, the actual effect of this sequence change is unknown.; In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Also known as 5185T>G; This variant is associated with the following publications: (PMID: 24772314, 22086652, 28888541, 28781887, 28277317, 21447777, 21990134, 25980754, 20516115, 17305420, 15235020, 19706752, 26777316, 21990165, 18992264, 27272900, 15172985, 30209399, 29446198, 30765603, 21473589, 17924331, 33087888, 32719484, 35665744, 25348405) -

Jul 25, 2023

Mayo Clinic Laboratories, Mayo Clinic

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PP5, PM2_moderate, PS3 -

Nov 03, 2022

Quest Diagnostics Nichols Institute San Juan Capistrano

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

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

Oct 02, 2015

Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

May 29, 2002

Breast Cancer Information Core (BIC) (BRCA1)

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Aug 31, 2012

Sharing Clinical Reports Project (SCRP)

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

BRCA1-related disorder Pathogenic:1

Apr 03, 2023

PreventionGenetics, part of Exact Sciences

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

Jan 21, 2025

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.5066T>G (p.M1689R) alteration is located in exon 16 (coding exon 15) of the BRCA1 gene. This alteration results from a T to G substitution at nucleotide position 5066, causing the methionine (M) at amino acid position 1689 to be replaced by an arginine (R). This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). In one published study, this mutation was shown to segregate with disease in a large 3-generation family (Mirkovic, 2004). This alteration has been classified as likely pathogenic (p>0.9889) by multifactorial analysis (Easton, 2007; Lindor, 2012). This amino acid position is well conserved in available vertebrate species. Functional analysis demonstrated that the p.M1689R alteration lead to a loss-of-function phenotype in both yeast and mammalian transcription assays (Mirkovic, 2004). Another functional study found that this nucleotide substitution is deleterious in a high throughput genome editing haploid cell survival assay (Findlay, 2018). This alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, this alteration is classified as pathogenic. -

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
DEOGEN2	Benign	0.39	.;T;.;.;T;.;.;.;T;.
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
MutationAssessor	Uncertain	2.9	.;M;.;.;.;.;.;.;.;.
PhyloP100		5.6
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
Mutation Taster		=0/100	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
Splicevardb		2.0
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

Other links and lift over

dbSNP: rs80357061; hg19: chr17-41219633;