rs80357104

Variant names:

• chr17-43063361-G-A
• rs80357104
• NM_007294.4:c.5165C>T

Your query was ambiguous. Multiple possible variants found:

• chr17-43063361-G-A
• chr17-43063361-G-C
• chr17-43063361-G-T

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM1 PM2 PP3_Moderate PP5_Very_Strong

The NM_007294.4(BRCA1):​c.5165C>T​(p.Ser1722Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000685 in 1,459,212 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: BRCA1 NM_007294.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:18 U:2 O:1
• Conservation: PhyloP100: 3.43

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 14 ACMG points.

• PM1: In a domain BRCT 1 (size 94) in uniprot entity BRCA1_HUMAN there are 74 pathogenic changes around while only 17 benign (81%) in NM_007294.4
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.848
• PP5: Variant 17-43063361-G-A is Pathogenic according to our data. Variant chr17-43063361-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 55441.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-43063361-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
BRCA1	NM_007294.4	c.5165C>T	p.Ser1722Phe	missense_variant	Exon 18 of 23	ENST00000357654.9	NP_009225.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
BRCA1	ENST00000357654.9	c.5165C>T	p.Ser1722Phe	missense_variant	Exon 18 of 23	1	NM_007294.4	ENSP00000350283.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.85e-7 AC: 1 AN: 1459212 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 726170

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000224

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: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:18 Uncertain:2 Other:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Breast-ovarian cancer, familial, susceptibility to, 1 Pathogenic:7 Uncertain:1 Other:1

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Brotman Baty Institute, University of Washington

Significance: not provided

Review Status: no classification provided

Collection Method: in vitro

- -

Apr 10, 2023

All of Us Research Program, National Institutes of Health

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This missense variant replaces serine with phenylalanine at codon 1722 in the BRCT1 domain of the BRCA1 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). Multiple functional studies have consistently shown that this variant results in the loss of transcription activation function of BRCA1 protein (PMID: 12496477, 15172985, 20516115, 30765603). This variant has been reported in at least six individuals affected with hereditary breast and/or ovarian cancer (PMID: 22476429, 33526602; Color internal data). An external laboratory has concluded this variant to be Pathogenic based on analysis of personal and family history of 44 probands (PMID: 25085752). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Pathogenic. -

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

- -

Feb 20, 2004

Breast Cancer Information Core (BIC) (BRCA1)

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

May 28, 2019

Mendelics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Apr 19, 2017

Counsyl

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Aug 17, 2012

Sharing Clinical Reports Project (SCRP)

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

May 25, 2017

Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.5165C>T (p.Ser1722Phe) variant in the BRCA1 gene has been reported in two patients in the Breast Cancer Information Core database (accession number 10462 and 10461). The variant has also been reported in additional patients by clinical laboratories in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/55441). Functional assays showed a strong deleterious effect [PMID 20516115]. This variant was not observed in the ExAC database. Serine at amino acid position 1722 of the BRCA1 protein is conserved in mammals. Although not validated for clinical use, computer-based algorithms SIFT and Polyphen2 predict this p.Ser1722Phe change to be deleterious. This variant thus classified as likely pathogenic. -

Mar 27, 2024

Baylor Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Hereditary breast ovarian cancer syndrome Pathogenic:4

Oct 02, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces serine, which is neutral and polar, with phenylalanine, which is neutral and non-polar, at codon 1722 of the BRCA1 protein (p.Ser1722Phe). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with breast cancer and/or ovarian cancer (PMID: 22476429, 28888541, 30093976, 35264596). ClinVar contains an entry for this variant (Variation ID: 55441). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is expected to disrupt BRCA1 protein function with a positive predictive value of 95%. Experimental studies have shown that this missense change affects BRCA1 function (PMID: 12496477, 20516115). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. -

May 11, 2021

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

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: BRCA1 c.5165C>T (p.Ser1722Phe) results in a non-conservative amino acid change located in the first BRCT domain (IPR001357) that binds ATM-phosphorylated proteins (e.g. abraxas, CtIP and BRIP1; see PMID 22193408). Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 251036 control chromosomes (gnomAD). c.5165C>T has been reported in the literature in individuals with personal and/or family history of breast- and ovarian cancer (Judkins_2005, Lu_2012, Chan_2018, Lynce_2020). Publications also reported experimental evidence, demonstrating decreased structural stability, impaired phosphopeptide binding and transcriptional activity (Lee_2010); and in a recent high throughput genome editing assay the variant resulted in a decreased (intermediate) function when testing it in a haploid human cell line whose survival is dependent on intact BRCA1 function (Findlay_2018). Ten other 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 (n=2) or likely pathogenic (n=8). Based on the evidence outlined above, the variant was classified as likely pathogenic. -

May 12, 2021

Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.5165C>T (p.Ser1722Phe) variant in the BRCA1 gene has been reported in two patients in the Breast Cancer Information Core database (accession number 10462 and 10461). The variant has also been reported in additional patients by clinical laboratories in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/55441). Functional assays showed a strong deleterious effect [PMID 20516115]. This variant was not observed in the ExAC database. Serine at amino acid position 1722 of the BRCA1 protein is conserved in mammals. Although not validated for clinical use, computer-based algorithms SIFT and Polyphen2 predict this p.Ser1722Phe change to be deleterious. This variant thus classified as likely pathogenic. -

Jan 23, 2020

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.Ser1722Phe variant in BRCA1 has been reported in at least 3 individual with breast cancer (Lu 2012, Breast Information Core (BIC) database). In addition, this variant has also been reported in ClinVar (Variation ID 55441) and was absent from large population databases. Computational prediction tools and conservation analysis suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. In vitro functional studies support an impact on protein function (Lee 2010, Carvalho 2002 ). In addition, this variant lies within a binding motif in BRCA1. In summary, although additional studies are required to fully establish its clinical significance, this variant meets criteria to be classified as likely pathogenic for autosomal dominant Hereditary breast and ovarian cancer. PM1, PM2, PP3, PS3_Supporting, PS4_Supporting -

not provided Pathogenic:3

Feb 04, 2025

GeneDx

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Observed in individuals with BRCA1-related cancers (PMID: 22476429, 30093976, 30264118, 30875412, 35264596); Published functional studies demonstrate a damaging effect with respect to protein folding, phosphopeptide binding activity and specificity, transcriptional activity, homology-directed repair, and cell viability (PMID: 12496477, 20516115, 30209399, 30765603, 35665744); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); Also known as 5284C>T; This variant is associated with the following publications: (PMID: 15172985, 30209399, 16267036, 20516115, 25085752, 12496477, 17305420, 22476429, 28781887, 15385441, 29446198, 23704879, 30264118, 30093976, 30765603, 31447099, 33087888, 30875412, 30787465, 33526602, 32377563, 35665744, 29884841, 33206196, 35264596, 33010199, 36260514, 28888541, 25348405) -

Mar 04, 2025

Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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Mar 29, 2021

Quest Diagnostics Nichols Institute San Juan Capistrano

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant has been reported in individuals and families affected with breast/ovarian cancer (PMID: 16267036 (2005), 22476429 (2012), 29446198 (2018), 30093976 (2018), 30264118 (2018), 31481248 (2019), 33010199 (2020)) and described as pathogenic based on a multifactorial likelihood algorithm in the published literature (PMID: 25085752 (2014)). In addition, functional studies describe the p.Ser1722Phe variant as having a deleterious effect on BRCA1 protein function (PMID: 12496477 (2002), 15172985 (2004), 20516115 (2010)). Based on the available information, this variant is classified as pathogenic. -

Hereditary cancer-predisposing syndrome Pathogenic:2 Uncertain:1

Dec 17, 2024

Molecular Diagnostics Laboratory, Catalan Institute of Oncology

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PM2_Supporting, PP3 c.5165C>T, located in exon 18 (19 according BIC nomenclature) of the BRCA1 gene, is predicted to result in the substitution of serine by phenylalanine at codon 1722, p.(Ser1722Phe). It is not present in the population database gnomAD v2.1.1, non cancer dataset (PM2_supporting). The variant, located in a (potentially) clinically important functional domain of BRCA1, is predicted to not have a significant impact on splicing by Splice AI and the BayesDel_noAF predictor score for this variant (0.4229) suggests a deleterious effect on protein function (PP3). However, it was reported by two or more calibrated studies with discordant results: Functional effect similar to pathogenic control variants (PMID:30765603) and between what was observed for benign and pathogenic control variants (PMID: 30209399), so PS3 and BS3 is not met. Moreover, several cases affected of breast and/or ovarian cancer carrying the variant are reported in the literature (PMID: 22476429, 33526602, 30093976, 30875412, 30264118, 35264596 and 2 internal cases), but there are no publications reporting cases of FA or cosegregations. In addition, the variant was also identified in the following databases: BRCA Exchange (Not yet reviewed), ClinVar (2x uncertain significance, 11x likely pathogenic, 7x pathogenic) and LOVD (2x uncertain significance, 1x pathogenic). Based on the currently available information, c.5165C>T is classified as an uncertain significance variant according to ClinGen-BRCA1 Guidelines version v1.0.0. -

Sep 02, 2024

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.S1722F pathogenic mutation (also known as c.5165C>T), located in coding exon 17 of the BRCA1 gene, results from a C to T substitution at nucleotide position 5165. The serine at codon 1722 is replaced by phenylalanine, an amino acid with highly dissimilar properties. Based on multiple structural and functional analyses, this alteration was shown to significantly alter protease sensitivity, peptide binding activity, peptide binding specificity, and transcriptional activity of the mutant protein compared to wild type (Mirkovic N et al. Cancer Res. 2004 Jun;64:3790-7; Lee MS et al. Cancer Res. 2010 Jun;70:4880-90). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. -

Nov 08, 2022

Color Diagnostics, LLC DBA Color Health

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This missense variant replaces serine with phenylalanine at codon 1722 in the BRCT1 domain of the BRCA1 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). Multiple functional studies have consistently shown that this variant results in the loss of transcription activation function of BRCA1 protein (PMID: 12496477, 15172985, 20516115, 30765603). This variant has been reported in at least six individuals affected with hereditary breast and/or ovarian cancer (PMID: 22476429, 33526602; Color internal data). An external laboratory has concluded this variant to be Pathogenic based on analysis of personal and family history of 44 probands (PMID: 25085752). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Pathogenic. -

Familial cancer of breast;C2676676:Breast-ovarian cancer, familial, susceptibility to, 1;C3280442:Pancreatic cancer, susceptibility to, 4;C4554406:Fanconi anemia, complementation group S Pathogenic:1

Jul 14, 2021

Fulgent Genetics, Fulgent Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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Malignant tumor of breast Pathogenic:1

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Department of Pathology and Laboratory Medicine, Sinai Health System

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

The BRCA1 p.Ser1722Ph variant falls within the BRCA1 C-terminus (BRCT) domain and was shown, in a yeast based transcription activation assay, to be temperature sensitive whereby activity was abolished at 37oC, and therefore likely represents a cancer-associated variant (Carvalho 2002). Lee et al (2010) used 3 biochemical and cell-based transcriptional assays to show that the variant had a strong functional effect and is likely associated with increased cancer risk. Other functional/computational models validated by such biochemical assays have also shown the variant to be deleterious (Mirkovic 2004, Karchin 2007). The variant was also identified in dbSNP (ID: rs80357104) “With other allele”, but no frequency information was provided, the variant was not identified in NHLBI Exome Sequencing Project (Exome Variant Server), Exome Aggregation Consortium (ExAC) or the 1000 Genomes Browser. The variant was present in the Clinvitae database, the ClinVar database (with conflicting interpretations of pathogenicity: classified as pathogenic by Sharing Clinical Reports Project derived from Myriad reports; uncertain significance by BIC, and classification not provided by Invitae), Fanconi Anemia Mutation Database (LOVD), COSMIC (1x in a cervical tissue/squamous cell carcinoma), the BIC database (2X with unknown clinical importance), and UMD (1X with a 3-UV ”unclassified variant”). The p.Ser1722 residue is conserved across mammals and most other organisms, and four out of five computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) suggest that the Phe variant may impact the protein; however, this information is not predictive enough to assume pathogenicity. In summary, based on the above information, this variant meets our laboratory’s criteria to be classified as likely pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.95
BayesDel_addAF	Pathogenic	0.46	D
BayesDel_noAF	Pathogenic	0.42
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.33	.;T;.;.;T;T;.;.;.;T;.
Eigen	Pathogenic	0.73
Eigen_PC	Pathogenic	0.68
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Uncertain	0.95	D;D;D;D;D;D;D;D;D;D;D
M_CAP	Pathogenic	0.78	D
MetaRNN	Pathogenic	0.83	D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Pathogenic	0.88	D
MutationAssessor	Pathogenic	3.0	.;M;.;.;.;.;.;.;.;.;.
PrimateAI	Uncertain	0.57	T
PROVEAN	Pathogenic	-4.5	D;N;.;D;.;.;N;D;D;D;D
REVEL	Pathogenic	0.76
Sift	Uncertain	0.0040	D;D;.;D;.;.;D;D;D;D;D
Sift4G	Uncertain	0.013	D;D;D;D;D;D;D;D;.;.;D
Polyphen		1.0, 1.0	.;D;.;.;.;D;.;.;.;D;.
Vest4		0.87
MVP		0.89
MPC		0.47
ClinPred		1.0	D
GERP RS		5.5
Varity_R		0.87
gMVP		0.87

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: rs80357104; hg19: chr17-41215378; COSMIC: COSV58794522; COSMIC: COSV58794522;