NM_007294.4(BRCA1):c.964G>C (p.Ala322Pro) AND Hereditary cancer-predisposing syndrome

Clinical significance:Conflicting interpretations of pathogenicity, Likely benign(1);Uncertain significance(1) (Last evaluated: Sep 5, 2018)

Review status:1 star out of maximum of 4 stars

criteria provided, conflicting interpretations

Based on:
2 submissions [Details]
Record status:
current
Accession:
RCV000218097.4

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
  • NM_007294.4:c.964G>C
  • 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]
Observations:
1

Condition(s)

Name:
Hereditary cancer-predisposing syndrome
Synonyms:
Neoplastic Syndromes, Hereditary; Tumor predisposition; Cancer predisposition; See all synonyms [MedGen]
Identifiers:
MONDO: MONDO:0015356; MedGen: C0027672

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Assertion and evidence details

Submission AccessionSubmitterReview Status
(Assertion method)
Clinical Significance
(Last evaluated)
OriginMethodCitations
SCV000277412Ambry Geneticscriteria provided, single submitter
Uncertain significance
(Sep 5, 2018)
germlineclinical testing

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

Citation Link,

SCV000903583Color Health, Inccriteria provided, single submitter
Likely benign
(May 18, 2017)
germlineclinical testing

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

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlineunknown1not providednot provided1not 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

Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.

Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, Grody WW, Hegde M, Lyon E, Spector E, Voelkerding K, Rehm HL; ACMG Laboratory Quality Assurance Committee..

Genet Med. 2015 May;17(5):405-24. doi: 10.1038/gim.2015.30. Epub 2015 Mar 5.

PubMed [citation]
PMID:
25741868
PMCID:
PMC4544753

Details of each submission

From Ambry Genetics, SCV000277412.5

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not provided1not providednot providedclinical testing PubMed (1)

Description

The p.A322P variant (also known as c.964G>C), located in coding exon 9 of the BRCA1 gene, results from a G to C substitution at nucleotide position 964. The alanine at codon 322 is replaced by proline, an amino acid with highly similar properties. This alteration was identified in a patient with renal cell carcinoma, and a functional comparison showed that this alteration displayed 82% homology-directed repair (HDR) function in comparison to wild type BRCA1 (Lu C et al. Nat Commun 2015; 6:10086). This amino acid position is not well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknown1not providednot provided1not providednot providednot provided

From Color Health, Inc, SCV000903583.1

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

Last Updated: Sep 18, 2021

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