NM_007294.4(BRCA1):c.964G>C (p.Ala322Pro) AND not provided

Clinical significance:Uncertain significance (Last evaluated: Mar 13, 2019)

Review status:2 stars out of maximum of 4 stars

criteria provided, multiple submitters, no conflicts

Based on:
2 submissions [Details]
Record status:
current
Accession:
RCV000483940.4

Allele description [Variation Report for NM_007294.4(BRCA1):c.964G>C (p.Ala322Pro)]

NM_007294.4(BRCA1):c.964G>C (p.Ala322Pro)

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.964G>C (p.Ala322Pro)
HGVS:
  • NC_000017.11:g.43094567C>G
  • NG_005905.2:g.123417G>C
  • NM_007294.3:c.964G>C
  • NM_007294.4:c.964G>CMANE SELECT
  • NM_007297.4:c.823G>C
  • NM_007298.3:c.787+177G>C
  • NM_007299.4:c.787+177G>C
  • NM_007300.4:c.964G>C
  • NP_009225.1:p.Ala322Pro
  • NP_009225.1:p.Ala322Pro
  • NP_009228.2:p.Ala275Pro
  • NP_009231.2:p.Ala322Pro
  • LRG_292t1:c.964G>C
  • LRG_292:g.123417G>C
  • LRG_292p1:p.Ala322Pro
  • NC_000017.10:g.41246584C>G
  • NR_027676.2:n.1141G>C
  • U14680.1:n.1083G>C
Protein change:
A275P
Links:
dbSNP: rs80357252
NCBI 1000 Genomes Browser:
rs80357252
Molecular consequence:
  • NM_007298.3:c.787+177G>C - intron variant - [Sequence Ontology: SO:0001627]
  • NM_007299.4:c.787+177G>C - intron variant - [Sequence Ontology: SO:0001627]
  • NM_007294.3:c.964G>C - missense variant - [Sequence Ontology: SO:0001583]
  • NM_007294.4:c.964G>C - missense variant - [Sequence Ontology: SO:0001583]
  • NM_007297.4:c.823G>C - missense variant - [Sequence Ontology: SO:0001583]
  • NM_007300.4:c.964G>C - missense variant - [Sequence Ontology: SO:0001583]
  • NR_027676.2:n.1141G>C - non-coding transcript variant - [Sequence Ontology: SO:0001619]

Condition(s)

Identifiers:
MedGen: CN517202

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Assertion and evidence details

Submission AccessionSubmitterReview Status
(Assertion method)
Clinical Significance
(Last evaluated)
OriginMethodCitations
SCV000566751GeneDxcriteria provided, single submitter
Uncertain significance
(Sep 19, 2018)
germlineclinical testing

Citation Link,

SCV001133659Quest Diagnostics Nichols Institute San Juan Capistranocriteria provided, single submitter
Uncertain significance
(Mar 13, 2019)
germlineclinical testing

PubMed (4)
[See all records that cite these PMIDs]

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod

Citations

PubMed

Application of embryonic lethal or other obvious phenotypes to characterize the clinical significance of genetic variants found in trans with known deleterious mutations.

Judkins T, Hendrickson BC, Deffenbaugh AM, Eliason K, Leclair B, Norton MJ, Ward BE, Pruss D, Scholl T.

Cancer Res. 2005 Nov 1;65(21):10096-103.

PubMed [citation]
PMID:
16267036

Analysis of missense variation in human BRCA1 in the context of interspecific sequence variation.

Abkevich V, Zharkikh A, Deffenbaugh AM, Frank D, Chen Y, Shattuck D, Skolnick MH, Gutin A, Tavtigian SV.

J Med Genet. 2004 Jul;41(7):492-507.

PubMed [citation]
PMID:
15235020
PMCID:
PMC1735826
See all PubMed Citations (4)

Details of each submission

From GeneDx, SCV000566751.5

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testingnot provided

Description

This variant is denoted BRCA1 c.964G>C at the cDNA level, p.Ala322Pro (A322P) at the protein level, and results in the change of an Alanine to a Proline (GCT>CCT). Using alternate nomenclature, this variant would be defined as BRCA1 1083G>C. This variant was observed in at least one individual undergoing clinical BRCA1 screening, with the clinical significance defined as undetermined (Judkins 2005). It was also identified in both tumor and normal surrounding tissue from an individual with clear cell renal cell cancer, with functional studies showing a decrease in homology-directed repair activity (Lu 2015). BRCA1 Ala322Pro was not observed at a significant allele frequency in large population cohorts (Lek 2016). This variant is located in a region known to interact with multiple proteins (Paul 2014). In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect. Based on currently available evidence, it is unclear whether BRCA1 Ala322Pro is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.

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

From Quest Diagnostics Nichols Institute San Juan Capistrano, SCV001133659.2

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (4)
#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknownnot providednot providednot providednot providednot providednot providednot provided

Last Updated: Jun 14, 2021

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