17-43067694-A-T

Variant names:

• chr17-43067694-A-T
• rs80357205
• NM_007294.4:c.4988T>A

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM1 PM5

The NM_007294.4(BRCA1):​c.4988T>A​(p.Met1663Lys) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000823 in 1,457,250 control chromosomes in the GnomAD database, with no homozygous occurrence. 2/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. M1663I) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 30)
  • Exomes 𝑓: 0.0000082 (0 hom.)
• Consequence: BRCA1 NM_007294.4 missense, splice_region
• Scores: Splicing: ADA: 0.007386
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:10 B:1
• Conservation: PhyloP100: 1.76
• Publications: 20 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: Uncertain_significance. The variant received 4 ACMG points.

• PM1: In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 15 benign, 84 uncertain in NM_007294.4
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr17-43067694-A-C is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 868096.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
BRCA1	NM_007294.4	c.4988T>A	p.Met1663Lys	missense_variant, splice_region_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.4988T>A	p.Met1663Lys	missense_variant, splice_region_variant	Exon 16 of 23	1	NM_007294.4	ENSP00000350283.3

Frequencies

GnomAD3 genomes Cov.: 30

GnomAD4 exome AF: 0.00000823 AC: 12 AN: 1457250 Hom.: 0 Cov.: 30 AF XY: 0.00000689 AC XY: 5 AN XY: 725268

African (AFR) AF: 0.00 AC: 0 AN: 33380

American (AMR) AF: 0.00 AC: 0 AN: 44712

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26110

East Asian (EAS) AF: 0.00 AC: 0 AN: 39662

South Asian (SAS) AF: 0.00 AC: 0 AN: 86156

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53390

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5750

European-Non Finnish (NFE) AF: 0.00000812 AC: 9 AN: 1107838

Other (OTH) AF: 0.0000498 AC: 3 AN: 60252

GnomAD4 genome Cov.: 30

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:10 Benign:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Breast-ovarian cancer, familial, susceptibility to, 1 Uncertain:3 Benign:1

Feb 10, 2011

Sharing Clinical Reports Project (SCRP)

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

May 02, 2016

Quest Diagnostics Nichols Institute San Juan Capistrano

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 07, 2016

Counsyl

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

This submission and the accompanying classification are no longer maintained by the submitter. For more information on current observations and classification, please contact variantquestions@myriad.com. -

Dec 23, 2003

Breast Cancer Information Core (BIC) (BRCA1)

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

not provided Uncertain:2

Jan 02, 2024

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Published functional studies demonstrate no damaging effect with respect to protein stability, protein folding, transcriptional activity, homology directed DNA repair, and phosphopeptide-binding activity (PMID: 20378548, 20516115, 35665744); In silico analysis is inconclusive as to whether the variant alters gene splicing; Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Also known as 5107T>A; This variant is associated with the following publications: (PMID: 17305420, 20516115, 20378548, 16267036, 26778126, 30209399, 35665744, 25348405, 25724305) -

Nov 10, 2017

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Hereditary cancer-predisposing syndrome Uncertain:2

Apr 30, 2024

Color Diagnostics, LLC DBA Color Health

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This missense variant replaces methionine with lysine at codon 1663 of the BRCA1 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function. Splice site prediction tools are inconclusive regarding the impact of this variant on RNA splicing. A minigene splicing assay reported the variant resulted in the skipping of exon 16 (BIC exon 17) (PMID: 25724305). Functional studies found conflicting results on the variant protein where it is reported to be normal in protease sensitivity, peptide binding and specificity and transcriptional activation assays (PMID: 20516115, 20378548) but abnormal in BRCT domain dimerization assays (PMID: 26778126) and in a haploid cell proliferation assay (PMID: 30209399). This variant has been detected in a breast cancer case-control meta-analysis in 1/60466 cases and 0/53461 unaffected individuals (PMID: 33471991; Leiden Open Variation Database DB-ID BRCA1_000361). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. -

May 09, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.M1663K variant (also known as c.4988T>A), located in coding exon 15 of the BRCA1 gene, results from a T to A substitution at nucleotide position 4988. The methionine at codon 1663 is replaced by lysine, an amino acid with similar properties. Functional studies and in silico predictions have previously shown that the p.M1663K alteration had low or no functional effect on protein level (Karchin R et al PLoS Comput Biol. 2007;16:3(2):e26; Rowling PJE et al J. Biol. Chem. 2010; 285(26): 20080–20087; Lee MS et al. Cancer Res. 2010; 70:4880-4890). In silico splice site analysis predicts that this alteration may weaken the native splice acceptor site, and using an in vitro mini gene assay, Alhborn LB et al. showed that the c.4988T>A (p.M1663K) alteration results in exon 17 skipping that leads to predominant production of an out-of-frame transcript with weak residual wild-type transcript representing only 7% of the total (Alhborn LB et al Breast Cancer Res Treat. 2015; 150(2):289-98). However, additional RNA studies have demonstrated that this alteration does not result in abnormal splicing in the set of samples tested (Ambry internal data). Further, 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), and a study using both in vitro and in vivo functional analyses found that this alteration disrupts the ability of BRCT to dimerize (Wu Q et al. Mol. Cell, 2016 Feb;61:434-48). This amino acid position is not well conserved in available vertebrate species. Based on the available evidence, the clinical significance of this variant remains unclear. -

not specified Uncertain:1

Jun 23, 2022

Genetic Services Laboratory, University of Chicago

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

DNA sequence analysis of the BRCA1 gene demonstrated a sequence change, c.4988T>A, in exon 16 that results in an amino acid change, p.Met1663Lys. This sequence change has not been described in population databases such as ExAC and gnomAD (dbSNP rs80357205). This sequence change has been reported in the Breast Cancer Information Core (BIC) database (PMID: 10923033). The p.Met1663Lys change affects a moderately conserved amino acid residue located in a domain of the BRCA1 protein that is not known to be functional. In-silico missense pathogenicity prediction tools (SIFT, PolyPhen2, Align GVGD, REVEL) provide contradictory results for the p.Met1663Lys substitution and functional studies have been inconclusive about the impact this sequence change has on the function of the BRCA1 protein (PMID: 30209399, 20516115, 20378548, 26778126, 30209399). However, in-silico splice prediction programs indicate this sequence change may affect normal splicing of the BRCA1 gene and an in vitro experimental study showed that it may lead to skipping of exon 16 (PMID: 25724305). Due to insufficient evidences. the clinical significance of the p.Met1663Lys change remains unknown at this time. -

BRCA1-related disorder Uncertain:1

Jun 21, 2023

PreventionGenetics, part of Exact Sciences

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The BRCA1 c.4988T>A variant is predicted to result in the amino acid substitution p.Met1663Lys. This variant was observed in the Breast Cancer Information Core (BIC) database (Szabo et al. 2000. PubMed ID: 10923033). This variant is interpreted as benign/uncertain in two studies of variant classification (Table S2, Findlay et al. 2018. PubMed ID: 30209399; Table 2, Judkins et al. 2005. PubMed ID: 16267036). Functional studies suggest that p.Met1663Lys variant does not affect the stability of the protein and has low functional effect (Figure 2, Rowling et al. 2010. PubMed ID: 20378548; Table 2, Lee et al. 2010. PubMed ID: 20516115). RT-PCR analysis suggests this variant predominantly leads to exon 17 skipping (Figure 2B, Ahlborn et al. 2015. PubMed ID: 25724305). This variant has not been reported in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. In ClinVar, this variant is interpreted as likely benign/uncertain (https://preview.ncbi.nlm.nih.gov/clinvar/variation/55349/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Hereditary breast ovarian cancer syndrome Uncertain:1

Jan 23, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces methionine, which is neutral and non-polar, with lysine, which is basic and polar, at codon 1663 of the BRCA1 protein (p.Met1663Lys). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with clinical features of BRCA1-related conditions (PMID: 10923033). ClinVar contains an entry for this variant (Variation ID: 55349). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be tolerated. Experimental studies have shown that this missense change affects BRCA1 function (PMID: 30209399). Studies have shown that this missense change alters mRNA splicing and is expected to lead to the loss of protein expression (PMID: 25724305). 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	0.093
BayesDel_addAF	Pathogenic	0.21	D
BayesDel_noAF	Uncertain	0.070
CADD	Benign	15
DANN	Benign	0.93
DEOGEN2	Benign	0.12	.;T;.;.;T;.;.;.;T;.
Eigen	Benign	-0.31
Eigen_PC	Benign	-0.24
FATHMM_MKL	Uncertain	0.86	D
LIST_S2	Benign	0.77	T;T;T;T;T;T;T;T;T;T
M_CAP	Pathogenic	0.76	D
MetaRNN	Uncertain	0.71	D;D;D;D;D;D;D;D;D;D
MetaSVM	Uncertain	-0.18	T
MutationAssessor	Benign	1.4	.;L;.;.;.;.;.;.;.;.
PhyloP100		1.8
PrimateAI	Benign	0.39	T
PROVEAN	Uncertain	-2.9	D;N;.;D;.;N;D;D;N;D
REVEL	Uncertain	0.63
Sift	Benign	0.28	T;D;.;T;.;D;T;T;T;D
Sift4G	Uncertain	0.018	D;D;D;T;D;D;D;.;.;T
Polyphen		0.0010, 0.32	.;B;.;.;.;.;.;.;B;.
Vest4		0.66
MVP		0.87
MPC		0.14
ClinPred		0.83	D
GERP RS		3.0
Varity_R		0.68
gMVP		0.46
Mutation Taster		=1/99	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.0074
dbscSNV1_RF	Benign	0.15
Splicevardb		3.0
SpliceAI score (max)		0.37		Details are displayed if max score is > 0.2
DS_AL_spliceai		0.37		Position offset: 1

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

Other links and lift over

dbSNP: rs80357205; hg19: chr17-41219711;