NM_007294.4(BRCA1):c.4735C>G (p.Pro1579Ala) AND not specified

Clinical significance:Likely benign (Last evaluated: Apr 10, 2019)

Review status:1 star out of maximum of 4 stars

criteria provided, single submitter

Based on:
1 submission [Details]
Record status:
current
Accession:
RCV000855579.1

Allele description [Variation Report for NM_007294.4(BRCA1):c.4735C>G (p.Pro1579Ala)]

NM_007294.4(BRCA1):c.4735C>G (p.Pro1579Ala)

Gene:
BRCA1:BRCA1 DNA repair associated [Gene - OMIM - HGNC]
Variant type:
single nucleotide variant
Cytogenetic location:
17q21.31
Genomic location:
Preferred name:
NM_007294.4(BRCA1):c.4735C>G (p.Pro1579Ala)
HGVS:
  • NC_000017.11:g.43071179G>C
  • NG_005905.2:g.146805C>G
  • NM_007294.3:c.4735C>G
  • NM_007294.4:c.4735C>GMANE SELECT
  • NM_007297.4:c.4594C>G
  • NM_007298.3:c.1423C>G
  • NM_007299.4:c.1423C>G
  • NM_007300.4:c.4798C>G
  • NP_009225.1:p.Pro1579Ala
  • NP_009225.1:p.Pro1579Ala
  • NP_009228.2:p.Pro1532Ala
  • NP_009229.2:p.Pro475Ala
  • NP_009230.2:p.Pro475Ala
  • NP_009231.2:p.Pro1600Ala
  • LRG_292t1:c.4735C>G
  • LRG_292:g.146805C>G
  • LRG_292p1:p.Pro1579Ala
  • NC_000017.10:g.41223196G>C
  • NR_027676.2:n.4912C>G
  • p.P1579A
Protein change:
P1532A
Links:
dbSNP: rs145466894
NCBI 1000 Genomes Browser:
rs145466894
Molecular consequence:
  • NM_007294.3:c.4735C>G - missense variant - [Sequence Ontology: SO:0001583]
  • NM_007294.4:c.4735C>G - missense variant - [Sequence Ontology: SO:0001583]
  • NM_007297.4:c.4594C>G - missense variant - [Sequence Ontology: SO:0001583]
  • NM_007298.3:c.1423C>G - missense variant - [Sequence Ontology: SO:0001583]
  • NM_007299.4:c.1423C>G - missense variant - [Sequence Ontology: SO:0001583]
  • NM_007300.4:c.4798C>G - missense variant - [Sequence Ontology: SO:0001583]
  • NR_027676.2:n.4912C>G - non-coding transcript variant - [Sequence Ontology: SO:0001619]

Condition(s)

Synonyms:
AllHighlyPenetrant
Identifiers:
MedGen: CN169374

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Assertion and evidence details

Submission AccessionSubmitterReview Status
(Assertion method)
Clinical Significance
(Last evaluated)
OriginMethodCitations
SCV000699171Women's Health and Genetics/Laboratory Corporation of America, LabCorpcriteria provided, single submitter
Likely benign
(Apr 10, 2019)
germlineclinical testing

PubMed (1)
[See all records that cite this PMID]

Citation Link

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlineunknownnot providednot providednot providednot providednot providedclinical testing

Citations

PubMed

Patterns and functional implications of rare germline variants across 12 cancer types.

Lu C, Xie M, Wendl MC, Wang J, McLellan MD, Leiserson MD, Huang KL, Wyczalkowski MA, Jayasinghe R, Banerjee T, Ning J, Tripathi P, Zhang Q, Niu B, Ye K, Schmidt HK, Fulton RS, McMichael JF, Batra P, Kandoth C, Bharadwaj M, Koboldt DC, et al.

Nat Commun. 2015 Dec 22;6:10086. doi: 10.1038/ncomms10086.

PubMed [citation]
PMID:
26689913
PMCID:
PMC4703835

Details of each submission

From Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV000699171.2

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (1)

Description

Variant summary: BRCA1 c.4735C>G (p.Pro1579Ala) 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 4.1e-06 in 246076 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. The possibility this variant is a rare polymorphism cannot be excluded. c.4735C>G has been reported in the literature in association with ovarian carcinoma (Lu_2015). This report does not provide unequivocal conclusions about association of the variant with Hereditary Breast and Ovarian Cancer. A co-occurrence with a pathogenic variant has been reported (BRCA2 c.9253dupA, p.Thr3085fsX26; LabCorp), providing supporting evidence for a benign role. The variant was also reported in the FLOSSIES database in a woman older than age 70 years who never had cancer, providing further supporting evidence for a benign role. Experimental evidence evaluating an impact on protein function demonstrated the variant to have similar activity to the wild-type following assessment via homology-directed repair (HDR) and transcriptional assays (Woods_2016, Lu_2015). Three ClinVar submissions from clinical diagnostic laboratories (evaluation after 2014) cite the variant as uncertain significance. One ClinVar submission (Invitae) indicates the variant co-occurred with a pathogenic BRCA1, further supporting a benign role. Based on the evidence outlined above, the variant was classified as likely benign.

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknownnot providednot providednot providednot providednot providednot providednot provided

Last Updated: Oct 8, 2021

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